Projects

Abstract

The process of drug discovery has long been characterized by inefficiency, high costs, and a low success rate. Over the past few decades, the traditional drug discovery pipelines, which heavily rely on trial-and-error experimentation and extensive pre-clinical testing in 2D cell line models, has proven to be a lengthy and expensive endeavour. Moreover, the average timeline for bringing a new drug to the market ranges from 10 to 15 years, with development costs averaging around $2.6 billion per approved drug. Furthermore, the most significant issue arises when these molecules progress to clinical trials, where more than 90% of them demonstrate limited efficacy as monotherapy treatment, highlighting the recent development trend towards combination therapies. Nonetheless, this high rate of failure not only represents a significant financial burden but also delays the delivery of potentially life-saving treatments to those in need. Concerning the unmet need for more efficient drug development programs and more potent treatment strategies, we developed an innovative discovery platform that integrates three innovative pillars namely: drug synergism, patient derived tumor organoids and AI-guided small molecule design. Using this integrated pipeline, we aim to efficiently develop novel small molecules that will work highly synergistic together (potentiators) with FDA approved drugs and in house developed small molecules. During the first phase (IOF-POC CREATE), we not only validated our artificial intelligence-driven algorithms but also generated and tested a number of new bioactive small molecules, resulting in positive outcomes (see preliminary data). With this IOF-POC DEVELOP project, we aim to transform our promising proof-of-concept data into a commercially attractive concept (spin-off: Sightera Biosciences) with a first-in-class lead candidate: SIGHT001-018.

Researcher(s)

• Promoter: Deben Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cholangiocarcinoma (CCA), an aggressive cancer of the epithelial cells of the bile ducts, is unfortunately often diagnosed in the late stage, leading to limited treatment options and subsequently to poor prognosis (5-year overall survival rates of 7-20%). Late-stage, unresectable disease is typically tested for FGFR2 fusions in tissue samples. However, diagnostic tissue samples often fail to capture the heterogeneity of the disease and may be inaccessible or risky to obtain. Liquid biopsies offer a promising minimally invasive alternative. While existing molecular techniques for gene fusion detection, such as FISH, RT-qPCR, and targeted RNA sequencing, have shown efficacy, they possess limitations in terms of speed, cost, multiplexing (i.e., simultaneous detection of different markers in the same sample), technical complexity and adaptability to liquid biopsies. To address these challenges, we propose a novel enzyme-free approach utilizing a singlet oxygen-based photoelectrochemical (1O2-PEC) platform for the fusion partner-agnostic detection of FGFR2 fusions in CCA patients. This platform offers high sensitivity, rapidity, ease-of-use, possibility for multiplexing, and is cost-effective. During the project, we will develop highly specific probes, evaluate their performance and determine the minimal sample preparation for tissue and liquid biopsies as a first push towards the routine clinical practice.

Researcher(s)

• Promoter: Koljenovic Senada
• Co-promoter: De Wael Karolien
• Co-promoter: Vandamme Timon
• Fellow: Arnouts Jorine

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pleural mesothelioma (PM) is a rare and highly aggressive tumor linked to asbestos exposure. Due to its non-specific presenting symptoms and the need for tissue biopsies, diagnosis of PM is delayed, negatively impacting prognosis. Moreover, PM treatment remains palliative due to chemo- and immunotherapy resistance. This emphasizes the need for earlier diagnosis and therapy resistance interception. This could improve patients' outcome, quality of life and even enable the possibility for new treatments. Therefore, in this project, I aim to tackle both late diagnosis and therapy resistance. First, I will construct a diagnostic and a predictive biomarker panel based on PM-specific molecular alterations (differentially methylated CpG sites and copy number alterations) that can be detected in liquid biopsies. The diagnostic biomarker panel is currently being validated. Using IMPRESS, our in-house developed detection technique, we will detect these biomarker panels in circulating tumor DNA, enabling rapid and minimally invasive tumor detection. Additionally, employing a multi-omics approach, I will identify molecular changes and dysregulated pathways associated with acquired chemo-immunotherapy resistance, in a unique patient cohort. These potential therapeutic targets can be used in further research on personalized treatments. Consequently, through this project, I aim to facilitate early diagnosis, minimize toxic side effects, and pave the way towards novel treatment options.

Researcher(s)

• Promoter: Op de Beeck Ken
• Co-promoter: Deben Christophe
• Co-promoter: Van Camp Guy
• Fellow: De Meulenaere Nele

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Cell and gene therapies are revolutionizing the way cancer is treated. CAR-T cell therapies have demonstrated the ability to induce durable remissions or even achieve cures in patients with certain blood cancers that were in final stages, including leukemia and lymphoma. Despite these hopeful results in hematological malignancies, the application of CAR cellular therapies has been more challenging in solid tumors. Solid tumors have a complex tumor microenvironment (TME) that creates barriers to immune cell infiltration and function. This immune-suppressive niche is low in nutrients, highly acidic and hypoxic (lacking oxygen) due to the aberrant metabolism of tumor cells and growth pattern of the tumor. Accumulating data indicates that T cells and NK cells entering this hostile environment are rendered dysfunctional. Up to 90 percent of adult cancers consist of solid tumors, presenting a big need for new therapies. With our research, we aim to enhance the therapeutic potential of NK cell therapies for solid tumor patients in need of new treatment options. NK cells are cytotoxic cells from the innate immune system that can recognize and eradicate tumor cells swiftly. Their distinct advantages over T cells, including a superior safety profile and potential for allogeneic therapy, make NK cell treatments more economically feasible and logistically appealing, thereby broadening patient accessibility. Until now, efforts to enhance NK cell efficacy in cancer therapy have mainly focused on blocking inhibitory receptors, CAR engineering, or cytokine stimulation. However, recognizing the profound impact of the TME on NK cell metabolism, recent approaches aim to combine immunotherapy with metabolic manipulation to bolster cellular function. This growing awareness underscores the need for innovative engineering and gene editing to develop resilient cellular products capable of thriving in the challenging TME. In this project, we seek to (1) unravel metabolic interventions that boost the metabolic and functional resilience of NK cells in a hypoxic environment; (2) employ CRISPR-Cas9 to stably engineer NK cells based on our discoveries, thereby unlocking their potential in hostile tumor environments; and (3) validate the improved killing capacity and fitness of NK cells in hypoxic conditions using state-of-the-art assays. Driven by the need for novel therapeutic strategies that enhance the overall outcome for cancer patients, we aim to create an innovative NK cellular therapy product that is metabolically rewired to withstand the harsh and suppressive TME.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Fellow: Verhezen Tias

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Advanced stages of head and neck squamous cell carcinoma (HNSCC) often face relapse or metastasis, and a miserable prognosis. First-line immunotherapy, with/without chemotherapy, displays limited benefits due to low response rates and severe side effects in weakened patients, compounded by high costs. In response, I will investigate an innovative, well-tolerable, and cost-efficient combination strategy to enhance approved therapies for this hard-to-treat cancer. Non-thermal plasma (NTP) is a localized ionized gas therapy that has been shown to activate the immune system and to induce cell death via disrupting the redox balance. To date, clinical use of NTP does not have reported major side effects. In addition, a well-tolerated, repurposed drug, shown to modulate immunity and redox metabolism, will be explored for its potential synergy with NTP. Therefore, I hypothesize that this combination, by altering redox balance, will enhance the effectiveness of (immuno)therapies for HNSCC through increased oxidative stress, cell death, and anti-tumor immunity. I will use 3D in vitro cancer models, primary patient material, and in vivo mouse models to evaluate the tumor kinetics, immune engagement, and therapy effectiveness. Successful completion of my project will lead to a combination strategy of NTP with repurposing drugs to improve the efficacy of first-line HNSCC therapies, while supporting the patient's quality of life.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Bogaerts Annemie
• Co-promoter: De Waele Jorrit
• Fellow: Bauwens Mauranne

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

COVID-19, a disease caused by an infection with SARS-CoV-2, has a broad range of clinical presentations varying from asymptomatic to severe bilateral pneumonia and even death. The risk to develop severe COVID-19 as well as the mortality is the highest in the elderly and in people with a pre-existing condition such as cancer. Hence, cancer patients were prioritized for COVID-19 vaccination even though data on the effectiveness and safety was not available as immunocompromised patients, like cancer patients, were excluded from vaccine approval trials. Since the approval of different COVID-19 vaccines, our group as well as many others performed studies to map the immunological responses of cancer patients after vaccination. In general cancer patients have reduced humoral immune responses after COVID-19 vaccination, nevertheless the vaccines are well-tolerated. As COVID-19 is evolving to be an endemic virus, it is important to map all parts of the vaccination-induced immune response. While most studies report IgG levels and neutralizing antibodies when investigating the humoral immunity, IgA antibodies are important for mucosal immunity and eliminate pathogens immediately at the point of entry (e.g. respiratory system). In the context of influenza, IgA serum levels have been correlated with influenza vaccine efficacy and influenza-specific IgA has been shown to be more effective in preventing infections in mice and humans compared with influenza-specific IgG. Therefore the level of IgA in serum may serve as an indicator of host immune response and might possible be a better predictor for protection against respiratory viruses compared to IgG, but studies on IgA production upon COVID-19 vaccination are lacking. Additionally, studies assessing the role of innate immune cells in vaccination-induced immune response are scarce. A recent study provided the first hints towards the predictive capacity of NK cells -innate lymphocytes that are crucial for mediating anti-viral responses- for vaccine-induced immunity in both healthy individuals and immunocompromised patients without cancer. This is in line with other research highlighting the potential of the activity level of NK cells to serve as a biomarker for a functional immune response, but as NK cells are involved in anti-tumor responses and might be affected by anti-neoplastic treatment, it is currently unknown if these findings can be applied in a cancer population. Hence, the aim of the current study is to gain a more in depth understanding of the different aspects of vaccination-induced immunity against SARS-CoV-2 in cancer patients focusing on both IgA levels and NK cells. This will help guiding COVID-19 vaccination strategies for cancer patients during future endemic outbreaks by providing knowledge on the state of the immune system of cancer patients and their response upon vaccination. Furthermore, the obtained insights can be used to improve vaccination strategies for cancer patients for other viruses as well as when novel viral pathogens emerge.

Researcher(s)

• Promoter: Vandamme Timon
• Co-promoter: Van Audenaerde Jonas
• Fellow: Debie Yana

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Our team proposes an innovative project integrating a 3D patient-derived pancreatic microtumor model with multi-omics analyses to dissect molecular mechanisms of Pancreatic ductal adenocarcinoma (PDAC) at a single-cell, patient-specific level. We aim to understand the intercommunication and reprogramming between malignant cells, stromal cells, and macrophages during PDAC progression by applying single-cell RNA-sequencing, secretomics and proteomics. Additionally, we will employ our AI-driven high-throughput drug screening platform to visualize live-cell interactions and study cell behavior in context. This setup allows us to scrutinize the biological and therapeutic impact of identified communication pathways by testing new therapeutic strategies on our microtumor model, thereby monitoring cell-specific responses. This groundbreaking research could revolutionize our understanding of PDAC, paving the way for the identification of new therapeutic targets and the development of effective treatments.

Researcher(s)

• Promoter: Deben Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, with a majority of the patients progressing towards recurrent/metastatic HNSCC with limited treatment options, underscoring an unmet clinical need. The observation that HNSCC is one of the most inflamed and immune infiltrated tumor types, with an exceptionally high infiltration of natural killer (NK) cells, supports the potential of NK cells as a therapeutic agent for this indication. Importantly, immunometabolism is pivotal to immune responses, including for NK cells, yet, how the tumor microenvironment affects NK cell metabolism is largely unknown and identifying NK cell evasion mechanisms could unlock both current and new therapies for HNSCC. We hypothesize that the deregulated metabolism of HNSCC cells is a pleiotropic hallmark in evasion to NK cells. We postulate that these metabolic resistance mechanisms are dual. On the one hand, metabolic reprogramming of HNSCC cells could mediate intracellular resistance to killing by NK cells. On the other hand, the metabolically deregulated HNSCC cells modify the metabolic composition of the tumor microenvironment, resulting in suppression of NK cells due to metabolite disbalance. This ultimately promotes immune evasion and jeopardizes survival of HNSCC patients. Unravelling these resistance mechanisms bear the potential to push NK cell therapies forward. To this end, we will perform multi-omics analyses, target identification, genetic engineering and pharmacological targeting, 2D and 3D in vitro experiments, in silico validation and in vivo testing. First, we will elucidate the linchpins of intracellular metabolic pathways in HNSCC cell driving resistance to NK cell-killing by conducting a CRISPR knockout screen using a metabolism-focused library and the top targets will be validated using patient datasets and functional assays. Second, we will unravel the effect of extrinsic metabolites, secreted by HNSCC cells, on NK cell-mediated killing. The key metabolites responsible for reduced NK cellular killing capacity will be identified and validated correspondingly. Finally, the potential of metabolic interference of these targets to boost the next generation NK cell therapy for HNSCC, i.e. chimeric antigen receptor (CAR) NK cells, will be determined in vitro and validated in vivo. Concluding, the proposed project will enrich our understanding of evasion mechanisms to NK cells and will expedite the breakthrough of next-gen NK cell therapy for head and neck squamous cell carcinomas, with high potential for implementation in additional solid tumors types.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: De Waele Jorrit
• Fellow: de Beukelaar Julie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Positioning of Project Adaptive radiotherapy (ART) was introduced in the late 20th century to adjust treatment margins based on imaging. Since then, technological advances have enabled the development of new treatment plans, either offline or in real-time (online ART). Offline ART modifies treatment plans between sessions, while online ART adapts the plan in real-time, keeping the patient on the treatment couch. This approach enhances tumor coverage and spares organs at risk (OAR) by adapting to anatomical changes such as tumor shrinkage or weight loss. Online ART systems are based on magnetic resonance or high-resolution cone-beam CT (CBCT) imaging to guide the adaptive process. They necessitate specialized linear accelerators, limiting their wider application. Robust planning, initially developed for proton therapy, challenges the traditional Planning Target Volume model by integrating organ motion and setup uncertainties directly into the treatment plan. This method optimizes plans across multiple deformed CTs, offering a more accurate approach than fixed-margin models. Although routinely used in proton therapy to address setup uncertainties, its use in photon therapy is underexplored. This research aims to: 1. Develop offline ART on non-specialized linear accelerators. Currently, no standardized guidelines or workflows exist for offline ART using CBCT imaging. This project will establish these guidelines, including automatic triggers for adaptation, and create a practical workflow for medical physicists based on imaging, surface scanning, and dose tracking. 2. Explore robust planning in photon therapy. Despite its potential to reduce the need for adaptation, robust planning has not been fully investigated in photon therapy. This study will bridge that gap by developing new methods for photon therapy planning. Methodology 1. ART Workflow Development and QA - Create, automate, and validate the ART workflow on a non-specialized linear accelerator. - Identify clinical scenarios where ART is most beneficial, incorporating CBCT, deformable registration, and dose calculation. - Perform Failure Mode and Effects Analysis (FMEA) for the online ART workflow and establish QA guidelines for Medical Physics Experts (MPEs). - Implement the ART workflow in clinical practice. 2. Identifying Patient Populations - Conduct a retrospective dosimetric analysis of patient cohorts, recalculating treatment plans under various scenarios: non-adapted, offline adapted, online adapted, and robustly planned. 3. Defining Adaptation Triggers - Determine key parameters (dose-related) that should trigger adaptation by analyzing data from patient positioning, plan complexity, and anatomical changes tracked via CBCT.

Researcher(s)

• Promoter: Verellen Dirk

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Surgery is the mainstay of treatment for oral cavity squamous cell carcinoma (OCSCC). Adequate resection margins (i.e. a minimum distance of 5 mm between the tumor and the surface of the resection specimen) are crucial for local disease control and prognosis. Inadequate tumor resection necessitates adjuvant (chemo) radiation or re-operation. Despite such adjuvant treatment the prospects of the patient are definitely diminished by inadequate margins. In addition, both radiation and chemotherapy may significantly affect the decreased quality of life. Unfortunately, the current rate of adequate OCSCC surgical results is only 15%. Clearly, the combination visual inspection and palpation with pre-operative imaging (e.g. CT, MRI), is insufficient to warrant adequate resections. To compensate this, a common intraoperative procedure for surgeons is to take tissue samples from the surgical wound bed for intraoperative pathological assessment of the resection margin. However, this so called frozen section procedure has many limitations; only a small proportion of the resection margin can be inspected in this way and the samples may not be representative. Moreover, here is no measurement of margin length, so close margins cannot be detected. More importantly, frozen section of the wound bed has not been unambiguously demonstrated to improve outcome. Intraoperative assessment of resection margins (IOARM) of OCSCC resection specimen has been proven to be the way forward. This approach has led to an immediate increase in the number of adequate resections from 15% to more than 50%. However, it is not realistic to expect that such laborious intraoperative assessment requiring a well-trained dedicated team of specialists can be widely adopted to become a standard of care. Therefore, an objective easy-to-use technique is needed, to accurately assess all resection margins intraoperatively. In this project, we propose the development of such a technique based on Raman spectroscopy. Raman spectroscopy is a non-destructive optical technique, which provides detailed information of the biochemical composition of a tissue, without the use of labels, dyes or reagents. Because malignant transformation is associated with changes in the biochemical composition of tissues, Raman spectroscopy can be used to distinguish a normal tissue from tumor. Recently, we have clearly shown that tissue water content is a powerful biomarker for discrimination between OCSCC and uninvolved oral structures. We have found the water concentration in OCSCC to be consistently higher than in the surrounding tissue. This new finding opens the way to new opportunities in intraoperative assessment of resection margins, in an objective and time-efficient manner.

Researcher(s)

• Promoter: Koljenovic Senada
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Vanderveken Olivier

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Prospects for cancer patients are certainly ameliorated in the past decade, especially thanks to the advances in the field of immunotherapy. However, it is important to note that many challenges remain. More specific, the majority of patients in need of better treatment options does not respond to immune checkpoint blocking therapy while CAR T cell therapy has only limited efficacy against solid tumours and on top causes severe side effects. Also, many tumours produce immunosuppressive cytokines like TGFβ, hampering current immunotherapy approaches. To address the challenges, our lab has developed over the past five years a TGFβ-resistant, Interleukin-15 producing CAR NK cell therapy which targets the CD70 protein. CAR NK cells have the important advantage that – contrary to CAR T cells – they do not cause severe side effects. Moreover, they can be produced as off-the-shelf therapy and do not require the same cumbersome production process as CAR T cells. The CD70 protein is also a ideal target since it is highly expressed in both leukaemia and solid tumours. This project has two main objectives. First, we want to gather the necessary preclinical data showing that our CAR NK cells are also successful against acute myeloid leukaemia. Secondly, we want to scale-up the production process of our CAR NK cells from research-grade to GMP-grade as this is a requirement for entering the clinical trial stage.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Campillo Davó Diana
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In high-income countries, more than 50% of cancer patients receive one or several courses of radiotherapy. Despite recent technological advances, especially in precision, tumour targeting and dose distribution, normal tissue exposure to ionizing radiation can be responsible for irreversible and debilitating long term side effects. Moreover, the sensibility of these organs at risk can substantially limit the dose escalation necessary to treat certain radiation resistant tumours, limiting the therapeutic impact of radiotherapy. For these reasons, preclinical research in radiotherapy has been focusing on new treatments and technologies that can prevent, mitigate or reverse radiation-induced side effects, without impairing antitumor efficacy. In this framework, recent observations made with the use of ultra-high dose rate (UHDR) "FLASH" radiotherapy (FLASH-RT), have shown the possibility to spare normal tissues from radiation-induced side effects. Indeed, the exposure of healthy tissues to radiation doses delivered at UHDR (> 100 Gy/s) was shown to induce significantly less side effects compared to conventional dose rate radiotherapy currently used in the clinics, while retaining a similar killing effect on tumour cells. This observation has since been coined the "FLASH effect". This normal tissue preservation was observed on multiple invertebrate and vertebrate organisms, including murine preclinical models of cerebral, skin, lung, gut, muscle, bone and hematopoietic toxicities but also on minipig skin. Moreover, veterinary clinical trials on cats and dogs domestic pets have shown promising results. These results led to the development of – currently 4, clinical trials in Switzerland and in the USA. This new technology raises multiple challenges in different disciplines: physics, chemistry, biology and clinics. Despite the publication of a large number of studies showing the advantages of FLASH radiotherapy, the lack of knowledge concerning the biological mechanisms explaining the FLASH effects drastically slows down its clinical translation. Similarly, the development of UHDR beams (protons, photons, electrons or ions) raises technological challenges concerning the production of such beams, dose measurement (dosimetry), dose distribution, treatment planning or radiation protection. Fundamental and translational research on UHDR FLASH-RT is blooming globally, and Belgium has become a major actor in this field. To our knowledge, at least 7 research institutes in Belgium are currently involved in UHDR research, including 4 centres equipped with dedicated UHDR beams, and one centre currently involved in a clinical trial. The impressive number of challenges and research questions related to this research field necessitate the development of close collaborations, in each discipline respectively, but also multidisciplinary actions, in order to reach a clinical application quicker and more efficiently. Some of these collaborations already exist (in physics for example) which allowed to create an initial network of research centres, willing to actively participate in the development of a better coordinated research activity.

Researcher(s)

• Promoter: Verellen Dirk

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Paediatric high-grade gliomas (pHGG) represent the leading cause of cancer-related death in childhood. With the current standard of care (SOC), the prognosis is very dismal with a 5-year survival rate of less than 20%. There is an urgent need to develop new treatment strategies to improve the overall survival. Immunotherapy to treat cancer is now considered to be one of the main pillars in cancer management and adoptive cell transfer has had enormous successes in the paediatric field in haematological malignancies. However, the therapeutic efficacy, as seen in haematological malignancies, has been lacking in solid tumours so far due to several challenges. pHGG are known for their cold immunological tumour microenvironment with few tumour infiltrating lymphocytes, have a high heterogeneity in antigen expression and are difficult to access due to the blood-brain barrier. Therefore, we aim to develop a novel therapy to overcome these challenges by combining the locoregional administration of our designed cell therapy with an immune priming strategy. We hypothesize that this combination therapy can increase the therapeutic efficacy of the SOC against pHGG.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Metastasis is the process by which cancer cells from a primary tumour can travel through the blood to other organs and form a second tumor. About one in four patients with colon cancer will experience metastases in the liver. All too often, patients die as a result of liver metastases. We do not yet know enough about how cancer cells form a metastasis in the liver. By looking at liver metastases with a microscope, we have observed that there are two patterns of tumour growth in the liver. We can determine these growth patterns when the metastatic lesion in the liver is removed by a surgeon and have found that one growth pattern is assocoated with a more favourable outcome for the patient when compred to the other. Although a colon cancer develops as a result of gene mutations, the behaviour of a tumour afterwards is controlled by additional changes within cancer cells that control how genes are turned on and off. We call these 'epigenetic' changes. We think the epigenetic characteristics of cancer cells that form the two distinct growth patterns of liver metastases are different. We will investigate this in liver metastases from patients with colorectal cancer. This will give us a better understanding of how the cancer cells are able to form a metastasis and thus allow us to think about treatments that are better adapted to each of the two growth patterns. This will eventually lead to a more effective treatment for patients with liver metastases.

Researcher(s)

• Promoter: Van Laere Steven

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

The aim of this project is to develop a novel, safe and ready-to-use therapy for the treatment of cancer patients. Therefore, we will test the efficacy of the novel therapy in the lab in different ways.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite screening campaigns, 8,000 people in Belgium are diagnosed with colorectal cancer annually. Of these, 25% of patients already have metastases at the time of diagnosis, and an additional 40% will develop metastases during their disease progression. The treatment of patients in an advanced stage mainly relies on multi-drug chemotherapies that can be combined with targeted therapies, but with limited success. This group of patients therefore needs new, improved treatments. In colorectal cancer, there is a close interaction between tumor cells and the tumor microenvironment, of which cancer-associated fibroblasts are the most common cells. These are also involved in the formation, growth, and migration of the tumor and can form a shield around the tumor that hinders the effect of systemic therapies. However, it has been found that not all cancer-associated fibroblasts contribute to tumor progression, and it is important to selectively target them. In our lab, we have discovered a subgroup of cancer-associated fibroblasts with a high expression of CD70 that are more common in advanced stages and are clearly associated with tumor migration and immune suppression. We are convinced that targeting these CD70+ cancer-associated fibroblasts can improve the efficacy of chemotherapy. In this project, I aim to investigate whether a CD70-targeted immune cell therapy can significantly improve the effect of first-line chemotherapies using state-of-the-art 3D culture models and an in-house developed drug screen imaging platform.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van den Eynde Astrid

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The process of drug discovery has long been characterized by inefficiency, high costs, and a low success rate. Over the past few decades, the traditional drug discovery pipelines, which heavily rely on trial-and-error experimentation and extensive pre-clinical testing in 2D cell line models, has proven to be a lengthy and expensive endeavour. Moreover, the average timeline for bringing a new drug to the market ranges from 10 to 15 years, with development costs averaging around $2.6 billion per approved drug. Furthermore, the most significant issue arises when these molecules progress to clinical trials, where more than 90% of them demonstrate limited efficacy as monotherapy treatment, highlighting the recent development trend towards combination therapies. Nonetheless, this high rate of failure not only represents a significant financial burden but also delays the delivery of potentially life-saving treatments to those in need. Concerning the unmet need for more efficient drug development programs and more potent treatment strategies, we developed the OdeXAI discovery platform that integrates three innovative pillars namely: drug synergism, patientderived tumor organoids and AI-guided small molecule design. Using this integrated pipeline, we aim to efficiently develop novel small molecules that will work highly synergistic together with FDA approved drugs and in house developed small molecules. With this IOF-POC CREATE project, we aim to validate the efficiency of the OdeXAI drug discovery platform. If successful, this synergy-based AI-driven drug discovery engine will inevitably contribute to faster and more efficient future combination therapy development.

Researcher(s)

• Promoter: Deben Christophe
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic cancer is one of the most lethal cancer types worldwide, with barely a quarter of the patients still alive one year after diagnosis and a 5-year overall survival below 10%. This dismal outcome is mainly due to its high resistance to all current therapies. Therefore, innovative and effective treatment options are urgently needed for these patients. The tumor microenvironment is stated as the major confounding factor involved in therapy failure. This tumor microenvironment acts as a dense fibrotic shield around the pancreatic cancer cells and additionally creates an immune suppressive environment. Therefore, combination therapies that target both cancer cells and modulate this immune suppressive tumor microenvironment are the next-generation strategies. Hence, in this project I will first modulate the fibrotic shield by using ormeloxifene. Subsequently, I will reinforce the patient's own immune system to eliminate pancreatic cancer cells by exploiting next-generation inhibitory immune checkpoints. With this rationally designed combination, I aim to provide a solid, scientific rationale to initiate a novel clinical trial for pancreatic cancer patients who are in dire need for new treatments options.

Researcher(s)

• Promoter: Quatannens Delphine

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The Research Council Prizes of the University of Antwerp are awarded every two years at the expense of the Special Research Fund University of Antwerp. They aim to honor a successful young postdoctoral researcher for a special contribution to his/her scientific field. J. De Waele is a laureate the Prize Vandendriessche.

Researcher(s)

• Promoter: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Despite advances in treatment options, conventional chemotherapy remains a pivotal part of NSCLC treatment, regardless of stage, even though it is accompanied with serious side effects and therapy-induced senescence (TIS). Cellular senescence is a durable cell cycle arrest and is characterized by the secretion of a strong pro-inflammatory senescence-associated secretory phenotype (SASP). Evidence indicates that TIS induces deleterious long-term effects including therapy resistance, disease progression, metastasis and recurrence. Thus, TIS acts as a barrier to complete eradication of the tumor, indicating the importance of targeting senescent cells during cancer therapy. Therefore, I will investigate a novel combination treatment in this project, specifically designed to eliminate therapy-induced senescent cells. Senescent tumor cells will be targeted by two strategies: senolytics to specifically kill these cells and senostatics to suppress or modulate the SASP. Moreover, I will identify the core senescent secretory profile of NSCLC, that will be used as a blood-based biomarker to identify and select patients that would benefit from our new senescence-focused therapy. The successful completion of my project will ultimately improve overall survival of NSCLC patients with a tumoral senescence signature, regardless of stage, by enhancing treatment efficacy and tumor eradication.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Deben Christophe
• Co-promoter: Lardon Filip
• Fellow: Verswyvel Jasper

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, with a majority of the patients progressing towards recurrent/metastatic HNSCC with limited treatment options. Despite the high natural killer (NK) cell infiltration, the efficiency of newly developed adoptive cellular therapies in clinical trials is limited. Therefore, I hypothesize that HNSCC cells secrete immunosuppressive metabolites in the tumor microenvironment (TME), exaggerated by the high level of hypoxia, inducing evasion to NK cells. Using physiologic and conditioned media at different oxygen levels, metabolic alterations in the TME are characterized by gas chromatography-mass spectrometry, providing high-value candidate metabolites that are later evaluated in a high-throughput screen to determine their effect on the NK cell killing capacity. Intracellular metabolic and functional changes of NK cells induced by exposure to the interfering metabolites are identified together with phenotypic profiling. Using an orthotopic humanized mouse model, NK cell functionality is investigated after modification of the TME and restoration of NK cell cytotoxicity combined with standard-of-care HNSCC treatment is evaluated. Concluding, this project will obtain fundamental insights into the suppressive role of hypoxia-induced metabolites on NK cells and will provide valuable knowledge for adoptive cellular therapies in development.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Fellow: Melis Jöran

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Inflammatory breast cancer (IBC) is a rare yet aggressive subtype of breast cancer, with a high mortality amongst others due to the lack of a specific treatment. The primary goal of this project is to strive towards a more comprehensive characterization of the tissue architecture and molecular complexity in IBC. This goal translates in two work packages. Firstly, we aim to investigate the communication between monocytes and B-lymphocytes, two cell types that are relevant to IBC biology based on available literature and our preliminary data. Secondly, using state-of-the-art technologies, we will Investigate the global composition of the tumor microenvironment in IBC beyond the cell types mentioned in the first aim. Then, the acquired knowledge of the composition of the tumor micro-environment and the molecular pathways of intercellular communication in IBC will be used to develop new strategies for targeted therapy. For this purpose, the use of preclinical models that optimally recapitulate tumor biology is quintessential. Therefore, this project will secondarily focus on the development of patient-derived tumor organoids (PDOs) that represent a significant advance for testing new treatment modalities. For this goal, again two work packages can be discerned. First, we aim to establish IBC PDOs that recapitulate the tissue architecture and molecular traits of primary IBC tissue samples as closely as possible. Secondly, we will use these organoid lines to test the efficacy of selected drugs in inducing cancer cell death and identifying predictive biomarkers of treatment response.

Researcher(s)

• Promoter: Van Dam Peter
• Fellow: Vermeulen Chloé

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Paediatric high-grade gliomas (pHGG) represent the leading cause of cancer-related death in childhood. With the current standard of care (SOC), the prognosis is very dismal with a 5-year survival rate of less than 20%. There is an urgent need to develop new treatment strategies to improve the overall survival. Immunotherapy to treat cancer is now considered to be one of the main pillars in cancer management and adoptive cell transfer has had enormous successes in the paediatric field in haematological malignancies. However, the therapeutic efficacy, as seen in haematological malignancies, has been lacking in solid tumours so far due to several challenges. pHGG are known for their cold immunological tumour microenvironment with few tumour infiltrating lymphocytes, have a high heterogeneity in antigen expression and are difficult to access due to the blood-brain barrier. Therefore, we aim to develop a novel therapy to overcome these challenges by combining the locoregional administration of our designed cell therapy with an immune priming strategy. We hypothesize that this combination therapy can increase the therapeutic efficacy of the SOC against pHGG.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Van Audenaerde Jonas
• Fellow: Vanheeswijck Liesbeth

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Neuroendocrine neoplasms (NENs) require regular assessment of tumor growth and treatment response. However, adequate, non-invasive tumor markers are currently lacking. Recently, we demonstrated that sequential genome-wide copy number alteration (CNA) profiling of circulating cell-free DNA (ccfDNA) could serve as novel, non-invasive biomarker in NEN patients. Expanding upon these findings, we will explore and benchmark a new analytical approach, GIPXplore, against the current gold standard for ccfDNA CNA analysis (ichorCNA). Moreover, aberrant methylation in ccfDNA will be analyzed using the novel, highly sensitive MSRE-smMIP-seq technology. Both methods for detection and quantification of tumoral DNA will be correlated to clinical outcomes in an extensive prospectively collected cohort of 250 NEN patients. This cohort will be established through the international collaboration between the Belgian ENETS CoEs and Dutch FORCE initiative. In doing so, we will validate the potential added value of ccfDNA analysis for clinical decision-making in NEN patients and facilitate clinical implementation.

Researcher(s)

• Promoter: Vandamme Timon

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Proteins are among the most important molecules in our cells and fulfill a whole series of different functions. They provide structure, are the enzymes in metabolic pathways, act as hormones, are secreted by immune cells etc… The structure of each protein is directly encoded by our genes and thousands of different proteins are present in our cell at any given time. Because of there important role, studying proteins in cancer cells or tissues can help understanding how cancer develop, provide leads for new therapy, or provide markers for detection of disease. To study all proteins in a cell (called the proteome) mass spectrometers are used. However, until recently these machines ware not fast and sensitive enough to analyze the proteins in a single cell or fully study how tumor cells interact with the immune system. With the TIMS-TOF mass spectrometer this now is feasible for the first time. In this project application we aim to acquire a Trapped ion mobility Q-Tof mass spectrometer hyphenated with a high throughput and robust nano-scale liquid chromatography instrument. The combination of which will provide us with a versatile tool that can be used for "single" cell proteomics and very sensitive HLA peptide analysis. In addition, in combination with the EVO-SEP one LC system, which is built for robustness and high throughput, the set-up is ideally suited for analysis of clinical samples (e.g. liquid biopsies) in general as up to 100 samples a day can be analyzed. This equipment will open new opportunities for the Center for Oncological Research (CORE) and help it in its mission to develop new detection and stratification methods and new revolutionary therapies for cancer.

Researcher(s)

• Promoter: Mertens Inge
• Co-promoter: Peeters Marc

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. SOCan will contribute to the (early) diagnosis and follow up of cancer via a new disruptive detection platform, i.e. singlet oxygen-based photoelectrochemical detection of cancer biomarkers. Those biomarkers are increasingly discovered and validated, but the detection necessitates rapid, accurate and sensitive devices. To achieve this, the combined use of electrochemical detection with light-triggered sensor technology for the specific and sensitive detection of pre-selected DNA and RNA cancer biomarkers is proposed. The application of this technology on tissue and liquid biopsy samples will be a major contribution to the early detection of cancer. SOCan aligns with the EU Mission on Cancer and will lead to an affordable and sensitive diagnosis of cancer, reducing the time to result which allows faster and specific treatment, and thereby saving lives.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Koljenovic Senada

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Neuroendocrine neoplasms (NENs) exhibit clinical and biological heterogeneity, making diagnosis extremely challenging. Moreover, NENs tend to progress slowly necessitating long-term follow-up to monitor tumor growth and response to therapy. Current modalities for diagnosis and follow-up of NENs are primarily based on imaging and (repeated) tissue biopsies, but these suffer from several shortcomings which has a direct impact on patients' lives. Over the past few years, liquid biopsies have gained interest as a minimallyinvasive way for rapid tumor detection and collection of molecular information of the tumor with circulating tumor DNA (ctDNA) as one of the most promising new markers. This ctDNA is the fraction of cellfree DNA (cfDNA) released by the tumor, that reflects both the genetic and epigenetic alterations of the tumor. Consequently, this project aims to leverage liquid biopsies to improve diagnostic accuracy in NENs and enable real-time monitoring of NEN patients. For this purpose, NEN-specific molecular alterations namely copy number alterations and differentially methylated CpGs will be identified and selected to enable detection and quantification of ctDNA. Since the gold standard detection methods, shallow whole genome sequencing and methylation arrays, respectively, are not capable to detect very low concentrations of ctDNA, two alternative and highly sensitive multiplex assays based on DNA sequencing and photoelectrochemistry, respectively, will be employed.

Researcher(s)

• Promoter: Vandamme Timon
• Fellow: Vandamme Timon

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Melanocytic skin lesions can either be benign or malignant. Although pathologic examination often provides a final diagnosis, in a number of cases the morphology is ambiguous and the malignant potential of the lesion cannot be determined. This uncertainty of the diagnosis has important consequences for the patients and the community. In case patients are incorrectly diagnosed with melanoma instead of a benign lesion, they will be subjected to unnecessary clinical examinations, psychological pressure and social disadvantages. On the other hand, patients with an incorrect diagnosis of a benign lesion instead of melanoma are insufficiently treated leading to a high risk of developing deadly metastatic disease. In this project we aim to technically verify and clinically validate a molecular assay to predict the malignant potential of ambiguous melanocytic lesions for which proof-of-concept has ready been established. This assay is based on genome-wide copy number variation (CNV) analysis. In a first phase we will finetune and standardize the proof-of-concept assay using a training set of 106 cases, enriched with ambiguous cases. The diagnostic accuracy and ideal cut-off will be determined and the performance of the assay will be verified in an independent test set of 76 ambiguous cases. The resulting assay, hereafter named AMELA assay (assay for Ambiguous MELanocytic skin lesions Analysis), will be validated in the second phase of the study. In a second phase a prospective, observational multicenter study will be conducted. Samples of 552 patients with ambiguous lesions will be included. The clinical performance (accuracy, sensitivity and specificity) of the assay will be determined based on adverse events during 2 years of follow-up. In addition, the robustness of the assay and the potential financial impact on the society will be assessed

Researcher(s)

• Promoter: Koljenovic Senada

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Precision oncology has been shown to greatly improve outcomes of cancer patients, with tailored treatment approaches that consist of patient-directed therapies on the molecular characteristics of a patient. Despite this, chemo- and radiotherapy are still the basis of most standard treatment regimens, especially for gastrointestinal (GI) cancer patients. Importantly, there are significant differences in how GI cancer patients respond to standard-of-care (SOC) chemotherapy (CT) and chemoradiation (CRT), resulting in a majority of patients experiencing either over- or undertreatment and a delay in starting the optimal treatment. Tailored treatment approaches for SOC CT/CRT to enable precision oncology for these standard therapies is of high interest in order to improve quality-of-life and survival of GI cancer patients. With no existing predictive biomarkers for CT/CRT, and genomic profiling falling short on this front, there is therefore a clear unmet medical need for a novel model that can distinguish CT/CRT responders and non-responders in GI cancer patients. Patient-derived tumor organoids (PDOs), a functional precision oncology strategy, are 3D vivo models generated from individual patient tumor tissue and have recently emerged as a promising tool for predicting CT/CRT responses in cancer patients. PDO-guided treatment has not yet been implemented in the clinic, because some limitations need to be overcome first. With this study, we aim to overcome the most important limitations by developing a multiparametric, live-cell imaging-based drug response signature for ex vivo PDO screenings that enables monitoring of the true PDO drug response. We hypothesize that this will drastically improve the predictive value of PDOs and feasibility of using PDO drug screenings in routine clinical practice. To test this and as proof-of-concept we will also perform a multicentric prospective observational cohort study with our novel PDO screening platform for prediction of neoadjuvant CT/CRT response in rectal and esophageal cancer patients in regional hospitals. If successful, we aim to set up a prospective clinical phase-1 trial in the future, and on the long term implement our PDO drug response signature as a tool to help guide clinical decision-making of CT/CRT treatment choices for GI cancer patients.

Researcher(s)

• Promoter: Prenen Hans
• Co-promoter: Deben Christophe
• Co-promoter: Komen Niels
• Fellow: Peeters Sofía
• Fellow: Seghers Sofie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In the past five years, RNA therapeutics have witnessed a true revolution. Several RNA-based therapies have been approved for the treatment of genetic diseases, with unprecedented successes, as in spinal muscular atrophy. Moreover, the past year showed the world that RNA-based therapies, namely mRNA vaccines, can be the answer to a worldwide pandemic and save the lives of millions. RNA therapies are however lagging behind in clinical oncology. The overarching aim of this multi-armed project is to develop RNA-based cancer treatments. In parallel, the development of immune checkpoint inhibitors has revolutionized cancer care, but its success remains limited to a subset of patients. Altogether, for 60 percent of the eight million new cancer patients diagnosed in Europe each year, including almost all children with solid tumors, there is no EMA- or FDA-approved immunotherapy option, and they are left out of the circle of hope. In response, CANCERNA aims to build on these two breakthroughs and apply RNA-based therapeutics to overcome key barriers to unfold successful anti-cancer immune responses. Our two key objectives are: on one hand, harness the modulation of RNA processing to enhance the accessibility and immune susceptibility of the tumour and its microenvironment. While on the other hand, enhance the activity of the immune system by retargeting immune effector cells and developing personalized mRNA vaccines. The project will focus on two cancer types: acute myeloid leukemia and uveal melanoma. The collective knowledge of our consortium of RNA scientists, clinicians and biotech-pharma experts in RNA processing, RNA drug design and delivery, biocomputing and immuno-oncology provides a unique opportunity to significantly advance novel RNA technologies into successful cancer therapies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

FLASH-RT, based on ultra-high dose rate irradiation (instantaneous dose rate above 104 Gy/s), recently became a hot topic in the field of radiation oncology. Several studies have recently shown that classical pathogenic patterns observed in normal tissues exposed to radiation delivered at conventional dose rate radiation therapy (CONV-RT) were not induced by single fractions of FLASH-RT, collective observations that we have since defined as the "FLASH effect". Published data forms a growing body of literature, documenting the marked normal tissue sparing found in multiple tissues (brain, lung, skin, gut) and in multiple mammalian species (mouse, cat, pig, rat) subjected to FLASH-RT (Favaudon 2014; Montay-Gruel 2017, 2018, 2020; Vozenin 2018; Alaghband 2020; Wilson 2020). These findings, along with data showing fully conserved anti-tumour efficacy and the first human trial (albeit for skin cancer) (Bourhis 2019, 2020) point to the exciting clinical promises of delivering FLASHRT in a large number of tumour sites. This previous research highlights the feasibility of translating preclinical studies into clinical trials for the treatment of cancers while limiting normal tissue toxicities. Therefore, the Iridium Kankernetwerk and the University of Antwerp is the first radiation oncology centre in Belgium, and the second in the world, to be equipped with the ElectronFlash irradiator developed by S.I.T. (Sordina IORT Technologies S.p.A., Italy - hereafter "S.I.T.") and thereby able to deliver ultra-high dose rate irradiation to attain the FLASH effect in preclinical circumstances. Currently, S.I.T. is developing a new accelerator for IOeRT, capable to deliver both CONV-RT and FLASH-RT. We should be the first centre in the world where this revolutionary machine for clinical applications will be installed, in the course of 2023, including CE-marking for clinical use. The preclinical research described in this project will consist in developing and using in vitro and in vivo tumour models to validate and optimize the treatment of breast tumour types using FLASH-RT. Therefore, our project aims at investigating the effect of FLASH-RT (compared to CONV-RT) on breast cancer and on radiation-induced skin, soft tissue, lung and heart toxicities. Up to now, while FLASH-RT has been found to prevent the development of radiation-induced toxicities on many different organs while keeping a good antitumour effect, no study has focused on its use for breast cancer treatment. The preclinical data obtained from this project is essential to ensure a safe and efficacious transfer of FLASH-RT to clinical breast cancer practice at the Iridium Kankernetwerk and University of Antwerp. Recent studies have suggested that the optimal FLASH effect was obtained with single dose exposures and with hypo-fractionated regimens (Bourhis 2019; Montay-Gruel 2020). This is compatible with IOeRT in both partial and whole breast irradiation settings, as this entails routinely the delivery of a single high dose of radiation (21 Gy for partial breast irradiation in low-risk patients; 9 Gy for a boost combined with routine whole breast irradiation in high-risk patients.

Researcher(s)

• Promoter: Meijnders Paul
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

The Center for Proteomics was founded about a decade ago as a UAntwerpen/VITO state-of-the-art mass spectrometry platform as a continuation of the former UAntwerpen CeProMa Core facility. Since 2017, the main focus of the UAntwerpen/VITO team was the use of proteomic approaches to identify biomarkers for early diagnosis of disease. Over the years, we have built up a multi-disciplinary team of lab technicians, mass spectrometry experts, biologists, biochemists, (bio)medical experts, mathematicians and (bio)-informaticians to set up good experimental designs, develop quality control tools, develop additional data analysis software, … Moreover, the close interactions we now have with clinical and academic partners (with complementary expertise and biobanks) give us access to high quality clinical samples and medical expertise. Today, we have the team's expertise, the network and the infrastructure that will help us bridge the gap between discovery, translation and clinical applications. Mass spectrometry based proteomics of biofluids and tissues is complementary to other techniques that are currently available at UAntwerpen. It has the advantage that it can detect modifications and discern various proteoforms. This is not possible with PCR based techniques and even new and promising techniques like single molecule protein sequencing have limitations compared to MS based techniques. Therefore, we make a combination of these techniques in our aim to create an as complete and accurate proteome profile as possible for (bio)medical applications. Besides proteomics, we also specialize in peptidomics, covering the analysis of naturally occurring small peptides which play important regulatory roles in all multicellular organisms and is especially relevant to study cellular interactions of the immune system. This type of analysis requires specialized technological skills, especially in terms of sample preparation, analytical techniques and data analysis. Some team members are worldwide pioneers in this field. This is the reason why several companies (J&J, MyNeo, …) collaborate with the CfP for exactly this type of expert scientific support. Thanks to investments from VITO and UAntwerpen (Hercules) we are equipped with state-of-the art mass spectrometers and hyphenated equipment that rival the best proteomics centers in Europe. Ours Tims-Tof mass spectrometer and Rapiflex maldi imager are unique in Flanders. With this proteomics and peptidomics platform, we focus on application driven research making it possible to work closer with the market than typical academic research groups do. This is a clear added value for both our University, VITO and the industrial partners.

Researcher(s)

• Promoter: Mertens Inge
• Co-promoter: Lemière Filip
• Co-promoter: Leroy Jo
• Co-promoter: Peeters Marc
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van Passel Steven

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

There is growing epidemiological evidence that onchocerciasis (river blindness) can cause epilepsy (onchocerciasis-associated epilepsy, OAE), a major unrecognized public health problem in sub-Saharan Africa. However, the pathophysiological mechanism remains unknown. Neither the Onchocerca volvulus, nor its endosymbiont Wolbachia, appear to be able to pass the blood brain barrier (BBB). Annual community-directed treatment with ivermectin (CDTI), has limited efficacy in reducing OAE incidence. Therefore, we will 1] Investigate in onchocerciasis-endemic areas, in Cameroon, whether a community based vector control method "slash & clear" combined with CDTI is superior to CDTI alone to decrease the incidence of OAE; 2] Explore whether O. volvulus excretory/secretory products can cross the BBB and possibly trigger OAE, by comparing proteomic profiles of cerebro-spinal fluid of children with OAE with those of different stages of the parasite; 3] Explore whether O. volvulus infected blackflies may transmit a neutrotropic virus causing OAE, by testing blackflies and sera from OAE cases with Q-PCR targeting potential OAE specific viral sequences identified during a metagenomic case-control study in South Sudan. Our findings will provide context-specific evidence about a complementary strategy to accelerate onchocerciasis elimination and new insights into the underlying mechanisms of OAE, and as such contribute to reducing the burden and stigma of 'river epilepsy'.

Researcher(s)

• Promoter: Mertens Inge
• Co-promoter: Colebunders Robert

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third deadliest cancer worldwide with an increasing incidence. The 5-year survival of 7% has barely changed in 50 years and is stated as the worst of any cancer type. The immunosuppressive tumour microenvironment is believed to be the major confounding factor involved in failure of current therapies. Because of the high medical need, we will investigate the potential of a novel personalised and modified chimeric antigen receptor (CAR)-natural killer (NK) cell therapy combined with an innovative immune-priming agent. More specifically, we will first modify NK cells using the revolutionary CRISPR-Cas9 technology to make them insensitive to transforming growth factor beta-mediated immunosuppression in the tumour microenvironment. Next, these ameliorated NK cells will be modified to target both the tumour and the surrounding tumour microenvironment using different CAR constructs. Additionally, to invigorate our CAR-NK cell therapy, we will combine this with an immunostimulatory agent. This not only has the capacity to broadly activate the immune system but can also induce a greater attraction of our CAR-NK cells into the tumour to make our CAR-NK cell therapy more efficient. Hence, supported by our encouraging preliminary data, we are convinced that this project has great potential to finally overcome the crucial hurdles that block the advancement of treatment options for PDAC patients.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Pauwels Patrick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) represents the third most common cancer type and second leading cause of cancer mortality worldwide. First-line standard treatment in metastatic CRC (mCRC) involves anti-EGFR therapy, which significantly improves progression-free survival (PFS) and overall survival (OS) in RAS/BRAF wild type patients. However, in this group of wild type patients, the response rate is only 30-50%. This indicates that additional resistance mechanisms exist that need to be discovered. Detection of resistance by conventional methods has several limitations. Therefore, there is a need for new, sensitive and specific biomarkers for mCRC management. Preliminary data have shown that methylated DNA biomarkers are promising in CRC detection and follow-up. in this project, I aim to identify differential methylation signatures that can predict primary anti-EGFR response and detect acquired resistance earlier than CT imaging. I will develop two multiplexed assays using droplet digital PCR. One assay will comprise primary resistance biomarkers, with the aim to develop a prediction test on tissue. Another assay will be developed for blood, where the acquired resistance biomarkers will be deployed as follow-up biomarkers allowing real-time monitoring of patients receiving anti-EGFR therapy. The overall aim is to improve the response prediction of these patients and bring us a step closer to personalized medicine.

Researcher(s)

• Promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: de Abreu Ana Regina

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Breast cancer (BC) and cervical cancer (BHK) patients, especially those with advanced disease, are in urgent need of new agents that improve survival and quality of life. One promising strategy is immunotherapy, but the cancer has developed mechanisms that circumvent its effects and benefit only a minority of patients. Recently, the RANK(L) signaling pathway is considered a significant mechanism, as it allows many cancers - including BK and BHK - to disrupt the communication of the immune cells and thus undermine the immune response. Supported by our initial results, we strongly believe that blocking this signal can override the immune system and improve susceptibility to immunotherapy. We therefore seek to reveal the most appropriate anti-RANK(L) immunotherapy to elicit an optimal anti-tumor immune response. Building on the results of our clinical studies, additional laboratory testing will allow us to identify that one, superior combination strategy, which we will further optimize in mouse models. Finally, this project will validate a novel imaging technique to select patients who will benefit from this therapy in order to minimize treatment and financial burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Lardon Filip
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This PhD project on neuroendocrine tumors (NET) in collaboration with the university hospital Antwerp (UZA) will consist of 2 research parts. 1. Translational research on neuroendocrine organoids, which is a relatively new model with the possibility of investigating various treatment options. These organoids have the same morphological, genetic and phenotypical features as the in vivo tumor and therefore are an important tool for preclinical and clinical research, but until recent there are only few studies ongoing with these organoids. Currently a pNET organoid biobank is created, developed in the UAntwerp and UZA, in collaboration with the Erasmus MC in Rotterdam, Netherlands. Through this biobank research will be conducted to test known resistance mechanisms against current cancer treatments and to develop new potential treatment options. Drug screening will be performed using the OrBITS platform, developed by CORE. 2. Clinical biomarker research, improving of new treatment options, quality of life of NET patients, prospective and retrospective clinical trials and data analyses. For this we will make use of the NETwerk and NETwork databases. Since 2017 NETwerk is a European reference center for NETs existing of various Flemish hospitals.

Researcher(s)

• Promoter: Peeters Marc
• Fellow: Islam Odeta

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with mesothelioma remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of only 5%. The current first-line chemotherapy, a combination of cisplatin and pemetrexed, only increases the overall survival by a few months. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are urgently needed in order to improve the prognosis and prolong the survival of mesothelioma patients. Smart combination strategies might improve anti-tumour response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. In this research project tumour-induced immunosuppression will be tackled via two different pathways: PD-L1 immune checkpoint blockade will be used to reactivate silenced anti-tumour immune responses while blockade of the VEGF/VEGFR signalling pathway will be used to target the tumour vasculature in order to reduce angiogenesis, thereby reducing tumour growth. In addition, we plan to assess the positive impact that exercise may have on this combination strategy. Both immune checkpoint blockade and targeted anti-angiogenic treatments have been shown to improve survival in various cancer types. In addition, in vivo work and beneficial immunomodulatory effects suggest the potential of exercise as a non-invasive intervention to increase tumour sensitivity and to potentially synergise with immunotherapies. Therefore, we hypothesize that these treatments will enhance each other's efficacy and will effectively slow tumour growth. Furthermore, we will be the first to investigate the effect of exercise as a co-therapy with immune checkpoint blockade and anti-VEGF. Our data will demonstrate whether exercise as a co-therapy might be beneficial for tolerance and efficacy of our selected combination strategy. Our preclinical study is necessary to investigate a possible synergy of this novel treatment strategy combining immune checkpoint blockade, an anti-angiogenic compound, and exercise. The aim of this project is to meet the urgent need for a new treatment strategy improving both overall survival and quality of life of mesothelioma patients. Since the treatment methods described in this project have already been approved for use in cancer patients, our data can be easily translated into a clinical study.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Marcq Elly
• Fellow: Rovers Sophie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Ultra-short pulsed high dose rate radiation therapy, known as FLASH, has recently created a serious ripple effect in the radiation oncology community. Pre-clinical data has shown single-pulse doses above certain thresholds to decrease normal tissue radiotoxicity with a factor of nearly two, and as such increasing the differential response between healthy and tumour tissue. The effect had already been described by Hornsey et al. in 1966, but a recent series of publications by the Franco-Swiss team from the Institut Curie (France) and Centre Hospitalier Universitaire Vaudois (CHUV, Switzerland) has revived the interest prompting various reviews and a special edition of the Radiotherapy and Oncology Journal dedicated to the topic [Vol 139, 2019]. Radiation oncology has been improved over the last century in a series of distinct evolutions from increasing photon energy from kV to MV, introducing proton therapy, the implementation of CT and 3D conformal radiation therapy including increasingly more accurate dose calculation algorithms, intensity-modulated radiation therapy, biological conformal radiation therapy, stereotactic (body) radiation therapy, and image-guided radiation therapy; all of which caused stepwise improvements in treatment outcome and toxicity. FLASH, once confirmed by independent pre-clinical research & clinical trials, has on the contrary the potential to cause a genuine revolution in the field. In all of this, precise dose-measurement is of tremendous importance to monitor and evaluate radiation delivery, which is essential for performing quality assurance in radiation oncology by monitoring, benchmarking and comparing treatment outcomes. This, up to now, is not yet available for FLASH-delivered radiation therapy. At this moment, there are still many questions to be addressed before we will be able to apply the FLASH effect in clinical practice. The radiobiological mechanism underlying the FLASH effect is still unknown and requires substantial pre-clinical research, which is not the primary focus of this project proposal. In addition, the dosimetry of FLASH beams poses considerable challenges due to the ultra-high dose rates (UHDR) per pulse. Modern radiation therapy operates at typical dose rates of 1 to 25 Gy per minute, whereas FLASH operates between 40 and 1000 Gy per second. Moreover, preliminary results indicate that the dose per pulse is more relevant than the average dose per (mili)second to induce this FLASH effect. Secondary standard ionization chambers, typically used for absolute dosimetry in a clinical setting, suffer from significant limitations and require large correction factors for charge collection inefficiencies in FLASH regimes. It comes to no surprise that dosimetric characteristics of these previous reports on the FLASH effect were based on alanine EPR and radiochromic dose assessments, both off-line solutions and presenting considerable uncertainties. The current project aims roexplore and identify the dosimetric challenges related to FLASH and contribute to standardized codes of practice in absolute dosimetry and dose reporting. With none of the available dosimetry techniques being developed to be operational within the extreme exposure conditions as faced with UHDR radiotherapy, it is the goal of this PhD project to - Challenge the existing dosimetry systems and further develop/improve them to have accurate and reliable dosimetry techniques for FLASH radiotherapy - Establish a UHDR-dedicated dosimetry protocol for both reference and online dosimetry

Researcher(s)

• Promoter: Verellen Dirk

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Both targeted and immunotherapies are the key to precision medicine for the treatment of cancer patients. Deregulated signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumourigenesis of multiple cancer types. Furthermore, it is well established that immune checkpoints are crucial for the tumour cell's escape from the immune system. The presence of drug resistance and/or immune evasion is a major obstacle to progress in the field. In our project, we will concentrate specifically on head and neck squamous cell carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Centre for Oncological Research (CORE) Antwerp. To date, there is still an urgent need to enhance the response to cetuximab treatment in recurrent/metastatic (R/M) HNSCC. Over the last years, cetuximab-related resistance mechanisms have been extensively studied at CORE. Based on our results and reports in literature, we hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. In the proposed project, we will investigate the potency of a novel triple combination strategy in order to enhance the response to cetuximab therapy in HNSCC patients. To achieve this, cetuximab will be combined with buparlisib, a selective PI3K inhibitor, and an immune checkpoint inhibitor. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. Furthermore, the nature of our project is translational, as from the beginning, we will use patient-derived HNSCC tumour organoids to validate our results from cell line experiments. These patient-derived tumour organoids are a very innovative and reliable model to identify effective treatment strategies and can actually be considered as a 'patient in the lab'. We are convinced that precision medicine using combinations of targeted therapies with immunotherapy may achieve the much-needed progress in HNSCC treatment. As reported in literature, both cetuximab and buparlisib treatment are able to promote anti-tumour immune response. Therefore, in the first work package, we will characterize the anti-tumour activity and immunomodulating effects of cetuximab in combination with buparlisib in HNSCC cell lines and patient-derived HNSCC organoids. Secondly, we will investigate the immunomodulating effects of cetuximab in combination with buparlisib on immune cells. In parallel, the effect of this combination treatment on the immune checkpoint profile will be assessed. Finally, the novel triple combination therapy consisting of cetuximab, buparlisib and an immune checkpoint inhibitor will be investigated in a humanized, PBMC engrafted HNSCC mouse model. This preclinical work will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the novel triple combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel triple combination strategy, we are confident that the data generated in this project will provide insight into how therapeutic response to cetuximab treatment can be optimized, thus favouring the setup of a successful clinical trial with the newly identified triple combination therapy.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The research activities of the consortium IPPON (Integrated Personalized & Precision Oncology Network) are at the forefront of integrated personalized cancer medicine, with emphasis on 1) developing novel and more effective therapeutic strategies; 2) an improved detection and understanding of mechanisms driving therapeutic resistance; and 3) identifying and validating biomarkers for early detection and personalized therapy, in different cancers in need for improved therapeutic outcomes. In this way, we aim to deliver the right treatment to the right cancer patient at the right time. Novel and emerging anticancer strategies that we investigate include - but are not limited to - locoregional perfusion, targeted therapy, immunotherapy, cold atmospheric plasma therapy as well as novel combination therapies. We are convinced that the interdisciplinary collaboration between basic, translational and clinical researchers, catalyzed through this consortium, will enable us to tackle burning research questions and clinical unmet needs to advance the field of personalized cancer medicine. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated clinical phase I/II oncological unit with a unique and complementary set of methods and skills covering the entire spectrum of molecular techniques, 2D and 3D cellular assays (in vitro and ex vivo), small- and large animal studies and clinical studies. IPPON gathers experts with an excellent research track record in fundamental, translational and clinical oncology; surgical techniques; targeted therapy; immunotherapy; (epi)genomics; (epi)transcriptomics; proteomics; imaging; liquid biopsies; pathology and clinical studies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Dewilde Sylvia
• Co-promoter: Hendriks Jeroen
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Smits Evelien
• Co-promoter: Van Dam Peter
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a research project awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Lardon Filip
• Promoter: Peeters Marc
• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumour that is associated with asbestos exposure. Due to its non-specific presenting symptoms and the need for imaging and tissue biopsies, diagnosis of MPM is delayed, thereby negatively impacting prognosis. Moreover, relapse from current treatments (chemotherapy, immunotherapy) is inevitable, making it palliative in intention. There is thus an urgent need for both earlier diagnosis and detection of chemotherapy resistance to improve patients' quality of life. Therefore, in this project, I aim to construct a diagnostic and a follow-up biomarker panel based on MPM-specific molecular alterations (copy number alterations (CNAs) and differentially methylated CpG sites) that can be detected in liquid biopsies. I already successfully established a patient-derived organoid model, which will be further optimised during this project. This model will eventually be used to detect genomic and methylomic alterations associated with chemotherapy resistance. Then, using a novel highly sensitive detection technique, the two biomarker panels will be detected in circulating tumour DNA of liquid biopsies, enabling rapid and minimally invasive tumour detection. Consequently, the goal of this project is to improve early diagnosis as well as enable patient follow-up during chemotherapy, in order to reduce unnecessary toxicity and futile treatment.

Researcher(s)

• Promoter: Op de Beeck Ken
• Fellow: De Meulenaere Nele

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite significant advancements in oncological treatments, many patients still succumb to the cancer, which remains the second leading cause of death worldwide. Novel treatment options are therefore urgently needed. The breakthrough of immunotherapy has revolutionized the field of oncology, however, the majority of patients remains unresponsive to immune checkpoint inhibitors. Armoured cellular therapies such as chimeric antigen receptor (CAR)-engineered T cells are now generating success in haematological malignancies, but comes with safety issues. Their lymphocytic counterpart, natural killer (NK) cells, are now presenting themselves as highly promising alternatives. Nonetheless, also NK cells remain ineffective against solid tumours. This is at least in part due to the hostile solid tumour microenvironment which impairs the metabolic and cytotoxic function of NK cells. Manipulating NK cells to withstand the vicious rigors of the tumour microenvironment could therefore be a gamechanger in their use as cell therapy against solid tumours. We discovered critical metabolic impairments in NK cells induced by tumour microenvironmental factors. We have found an actionable metabolic target to manipulate NK cells either pharmacologically or genetically, resulting in protection of their cellular health and cytotoxic function. With this IOF-POC project, we aim to validate and expand our patented claims in multiple solid tumour models on different levels and find industrial partners to proceed its valorisation route. Ultimately, our strategy to protect the fitness of NK cells in the tumour microenvironment could enable the efficacious application of CAR-engineered NK cell products for solid malignancies, and as such impact many cancer patients.

Researcher(s)

• Promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Over the last decade, immunotherapy has had an unseen impact on the outcome of cancer patients. However, many hurdles remain. For example, the majority of patients in need of better treatment options does not respond to PD-1 blockade, while CAR-T cells remain ineffective in solid tumours as monotherapy and go hand-in-hand with often severe cytokine release syndrome and neurotoxicity. On top of that, most tumours produce large amounts of cytokines in their microenvironment which fiercely suppresses both present and infiltrating immune cells. To address these obstacles, our lab has developed over the last five years a CAR-NK cell therapy which targets the CD70 protein. CAR-NK cells have the advantage over CAR-T cells of being safer since no toxicities were observed in their first clinical trials and their ability to be produced off-the-shelf. Moreover, we have proven that CD70 is a highly attractive target for several cancer types and is on top more and more recognised as a promising pan-cancer target. For this project, two main objectives have bene formulated: first we want to optimise the production process of the CAR-NK cells in such a way that they are being produced according to GMP regulations. The latter is necessary to allow usage in a clinic trial. Secondly, we want to collect the necessary preclinical data proving the effectiveness of our CD70 CAR-NK cell therapy in acute myeloid leukaemia. This way, we want to formulate a GMP-grade, as automated as possible, CAR-NK production process and have acquired all required preclinical data necessary to start an early-phase clinical trial.

Researcher(s)

• Promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cellular cancer immunotherapy is on the rise to follow the footsteps of immune checkpoint inhibition as cancer immunotherapy breakthrough, yet only shows efficacy in haematological malignancies. Indeed, solid tumours impose various challenges on immune cells. Their tumour microenvironment (TME) is a metabolic wasteland that impairs effector immune cell functioning. Central in this TME is hypoxia, which is now recognized as barrier to immunotherapy due to effects on both tumour and immune cells. In this project, we focus on natural killer (NK) cells as effector immune cells with great potential as adoptive cell product due to inherent cytolytic capacities as well as safety and logistics profiles. Nonetheless, even when armoured with chimeric antigen receptors (CAR), NK cells fail to fully exert their function in hypoxia. Here, we will characterize and validate our lead for the development of (CAR) NK cells proficient in the hypoxic TME. This could propagate the development of next-generation of metabolically enhanced CAR NK cells against solid tumours.

Researcher(s)

• Promoter: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This PhD project on neuroendocrine tumors (NET) in collaboration with the university hospital Antwerp (UZA) will consist of 2 research parts. 1. Translational research on neuroendocrine organoids, which is a relatively new model with the possibility of investigating various treatment options. These organoids have the same morphological, genetic and phenotypical features as the in vivo tumor and therefore are an important tool for preclinical and clinical research, but until recent there are only few studies ongoing with these organoids. Currently a pNET organoid biobank is created, developed in the UAntwerp and UZA, in collaboration with the Erasmus MC in Rotterdam, Netherlands. Through this biobank research will be conducted to test known resistance mechanisms against current cancer treatments and to develop new potential treatment options. Drug screening will be performed using the OrBITS platform, developed by CORE. 2. Clinical biomarker research, improving of new treatment options, quality of life of NET patients, prospective and retrospective clinical trials and data analyses. For this we will make use of the NETwerk and NETwork databases. Since 2017 NETwerk is a European reference center for NETs existing of various Flemish hospitals.

Researcher(s)

• Promoter: Peeters Marc
• Fellow: Islam Odeta

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Despite advances in treatment options, conventional chemotherapy remains a pivotal part of NSCLC treatment, regardless of stage, even though it is accompanied with serious side effects and therapy-induced senescence (TIS). Cellular senescence is a durable cell cycle arrest and is characterized by the secretion of a strong pro-inflammatory senescence-associated secretory phenotype (SASP). Evidence indicates that TIS induces deleterious long-term effects including disease progression, metastasis and recurrence. Thus, TIS acts as a barrier to complete eradication of the tumor, indicating the importance of targeting senescent cells during cancer therapy. Therefore, I will investigate a novel combination treatment in this project, specifically designed to eliminate therapy-induced senescent cells. Senescent tumor cells will be targeted by two strategies: senolytics to specifically kill these cells and senostatics to suppress or modulate the SASP. Moreover, I will identify the core senescent secretory profile of NSCLC, that will be used as a blood-based biomarker to identify and select patients that would benefit from our new senescence-focused therapy. The successful completion of my project will ultimately improve overall survival of NSCLC patients with a tumoral senescence signature, regardless of stage, by enhancing treatment efficacy and preventing relapse.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Deben Christophe
• Co-promoter: Lardon Filip
• Fellow: Verswyvel Jasper

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC) are two of the most common and lethal malignancies worldwide. Survival outcomes for the majority of these patients remain very poor due to an advanced stage at diagnosis and their rapid progressive nature. The first-line treatment of advanced NSCLC in most patients still consists of conventional chemotherapy to achieve tumor response or stable disease. Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine/nab-paclitaxel or FOLFIRINOX which have only modest improvements in survival due to chemoresistance in most patients. Therefore, there is a high unmet need for novel and more effective treatment approaches for both cancer types. This dire need for new therapeutic options encouraged me to provide the fastest way towards clinical application. Therefore, we used the orally available, lipophilic, organogold compound Auranofin (AF), which is included in the list of the ReDo (Repurposing Drugs in Oncology) project established by the Belgian non-profit Anticancer fund. I was the first to show the therapeutic anticancer potential of AF in mutant p53 NSCLC and PDAC cancer cell lines in which it triggered distinct molecular cell death mechanisms (apoptosis, ferroptosis and immunogenic cell death) by inhibiting the thioredoxin and glutathione redox systems and inducing oxidative stress (Freire Boullosa et al., 2021). Furthermore, I showed the relevance of targeting thioredoxin reductase in NSCLC patients, since it is overexpressed in NSCLC cells compared to the surrounding tissue. Despite these promising results as a single agent, I am convinced that the true power of AF lies within rationally designed drug combination strategies. This is supported by my recent work on the highly synergistic combination of AF and the PARP-1 inhibitor Olaparib which is effective in in vitro and in vivo NSCLC and PDAC models (ongoing). In addition, an increasing number of publications highlights the potential of AF in combination with chemotherapeutic agents, mTOR inhibitors, ROS inducers, etc. which resulted in several Phase I and II clinical trials. Therefore, the goal of this study is to perform a high-throughput drug combination screening with AF and a literature-based / clinically available drug panel based on standard of care regimens and inhibitors of KRAS effector pathways, in a set of patient-derived NSCLC and PDAC 3D organoids using our in-house developed drug screening platform Orbits. This allows us to study for the first time which AF drug combination strategies are the most promising and which baseline patient characteristics are related to therapy response using the most clinically relevant in vitro model available to date based on the genomic and transcriptomic characterization of these organoid lines. Overall, drug repurposing of the off-patent drug AF will contribute to a positive impact on patient outcome and quality of life, to a faster clinical implementation and to a lower healthcare cost.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

COVID-19 is a disease caused by an infectious outbreak of SARS-CoV-2. It was first reported in the City of Wuhan, People's Republic on 31 December 2019. Today, the virus is widely spread throughout the world and declared by the World Health Organisation (WHO) as a pandemic. There are a broad range of clinical presentations of a viral SARS-CoV-2 infection, ranging from asymptomatic, sensation of a mild cold or flu to severe bilateral pneumonia and death. Cancer patients are at high risk to develop serious illness after infection with SARS-CoV-2. Therefore, it is of high importance to protect these patients by following hygiene measurements and social distancing. But, as indicated by the guidelines of the Belgian and European Society for Medical Oncology, it is also important to vaccinate cancer patients. Although, not many studies that investigated the vaccine efficacy of COVID-19 vaccines in cancer patients have been performed. Due to the cancer or the treatment, it could be possible that the efficacy of the vaccines is lower in cancer patients or that they develop more side effects as a result of vaccination. To investigate this, we will monitor the reaction of the immune system of current and ex oncological and haematological patients on the different COVID-19 vaccines (Pfizer, Moderna, AstraZeneca, Janssen Pharmaceutica). The adverse effects as a reaction on vaccination will be investigated in this population as well. Clinical data of the patients will be collected and a blood drawn will be performed at different time points: before vaccination and 4, 6 and 12 months after receiving the first vaccination dose. The blood samples will be used to determine the amount and efficacy of the antibodies against SARS-CoV-2. Patients will also be asked to report side effects after vaccination. This will be done with a questionnaire that will be sent to the patients three days after each vaccination. The primary endpoint of the study is the quantification of different anti SARS-CoV-2 specific IgG antibodies per study cohort at 4 months after the first vaccination. Depending on the availability, antibody titers will be quantified using a MULTIPLEX SARS-CoV-2 Immunoassay, Siemens Healthineers Atellica IM SARS-CoV-2 IgG (sCOVG) assay or an in-house developed anti-RBD ELISA (Sciensano). The secondary endpoints of the study are to investigate the evolution and duration of the immune response after vaccination in the patient cohort using serological assays to analyse anti-RBD IgG titers 12 months after the first vaccination. Another secondary endpoint is to analyse the titers of neutralizing antibodies both 4,6 and 12 months after receiving the first vaccination dose. Furthermore, it is aimed to investigate the efficacy of the immune response in the patient cohort for each different vaccine. This will be assessed by the SARS-CoV-2 infection rate based on information collected through questionnaires on incidence of (PCR-confirmed or chest CT scan confirmed) SARS-CoV-2 infection within a time frame of 12 months after the start of the study. At last, we will investigate the safety of the different COVID-19 vaccines that are commercially available in Belgium. Safety will be reported in terms of incidence and severity of adverse effects (AEs) using a questionnaire which will be sent via REDCap. Patients will be asked to enter their adverse events over a period of 3 days after the vaccination day. If the patient does not have an email address, the questionnaire can be completed on paper. Only patients who had their baseline visit prior to their vaccination will be asked to complete these questionnaires. To end, serious vaccine-related adverse events which lead to hospitalization or further examination will be reported in the eCRF. This research project will provide knowledge on how the immune reaction after vaccination develops in cancer patients and patients with oncological or haematological history.

Researcher(s)

• Promoter: Peeters Marc
• Fellow: Debie Yana

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Over the last few decades, most of our knowledge regarding the biology and treatment of cancer has been derived from in vitro and in vivo tumor models. The use of 2-dimensional (2D) cancer cell lines has been considered as the golden standard in both basic and translational oncological research. Unfortunately, 2D in vitro models are not able to recapitulate the complexity and cellular heterogeneity of the in vivo setting. Moreover, numerous studies have demonstrated that 2D in vitro models fail to prospectively predict individual treatment responses. Accordingly, the inevitable limitations of pre-existing cancer models in combination with the urgent need for more physiologically relevant predictive platforms have eventually fostered the development of patient-derived tumor organoids. These three-dimensional (3D) multicellular constructs do not only hold great promise to elucidate the underlying molecular mechanisms of cancer growth (basic and translational relevance), but also significantly enhance the concept of personalized medicine (clinical relevance). Moreover, the main advantage of using patient-derived tumor organoids is their preservation of the genetic profile, cellular heterogeneity and clinical response of the primary tissue they originate from. Combining these auspicious features with their high-throughput potential, provides this tool promising applications for future cancer research. In accordance with this promising future, our group recently developed a more advanced pancreatic ductal adenocarcinoma (PDAC) organoid in vitro model (i.e. micro-tumor platform) that incorporates a stromal compartment. Given the numerous advantages of this innovative in vitro platform (compared to the traditional organoid cultures), we are convinced that this model will be the seed for a novel era in preclinical and clinical oncological research. Nevertheless, it should be addressed that, prior to its implementation, further research is of unmet need. Accordingly, this project will focus on validating the physiological relevance of this micro-tumor platform by comparing the concordance in terms of transcriptional profile and fibroblast heterogeneity between our platforms and parental tumors (N=7). Additionally, we aim to comprehensively characterize each micro-tumor (activated pathways, proteome, secretome, single cell transcriptome) and map the bi-directional communication/rewiring of both the PDAC and stromal cells in a co-culture setting. To explore this crosstalk, we will combine a single-cell RNA-seq analysis with a mass spectrometry analysis and subsequently implement the state-of-the-art bioinformatic algorithms (CytoTalk and CellRank). In the end, this validation study allows the previously planted seed to sprout and find its way towards the upcoming era of oncological research.

Researcher(s)

• Promoter: Deben Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Breast cancer is one of the deadliest cancers in women and especially the aggressive subtypes such as triple-negative breast cancer (TNBC) are difficult to treat. Although the immune system provides a natural barrier against invading and metastasizing breast tumor cells, it often fails to halt the disease progression due to immunosuppressive activity orchestrated by breast tumor cells and surrounding stromal cells. The protein chitinase 3-like 1 (CHI3L1) has been highlighted as a potential immunotherapeutic target in cancer due to its stimulation of immunosuppression and metastasis, but its role in breast cancer and more specifically TNBC, remains to be unraveled. This project will investigate the involvement of CHI3L1 signaling in TNBC progression, lymphatic development and dissemination as well as inflammation of triple-negative breast tumors using an in-house characterized immunocompetent intraductal mouse model and clinical samples from TNBC patients. We will also examine the therapeutic effect of CHI3L1 blockade and assess whether such inhibition synergistically enhances the clinical efficacy of immunotherapeutic treatments in TNBC. The results of this project will unequivocally demonstrate if CHI3L1 blockade can be used as an effective TNBC treatment strategy, potentially in combination with other immunotherapies, providing a response to the high clinical demand for better TNBC therapeutics.

Researcher(s)

• Promoter: Van Laere Steven
• Fellow: Steenbrugge Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

COVID-19 is a disease caused by an infectious outbreak of SARS-CoV-2. It was first reported in the City of Wuhan, People's Republic on 31 December 2019. Today, the virus is widely spread throughout the world and declared by the World Health Organisation (WHO) as a pandemic. There are a broad range of clinical presentations of a viral SARS-CoV-2 infection, ranging from asymptomatic, sensation of a mild cold or flu to severe bilateral pneumonia and death. Cancer patients are at high risk to develop serious illness after infection with SARS-CoV-2. Therefore, it is of high importance to protect these patients by following hygiene measurements and social distancing. But, as indicated by the guidelines of the Belgian and European Society for Medical Oncology, it is also important to vaccinate cancer patients. Although, not many studies that elevated the vaccine efficacy of COVID-19 vaccines in cancer patients have bene performed. Due to the cancer or the treatment, it could be possible that the efficacy of the vaccines is lower in cancer patients or that they develop more side effects as a result of vaccination. To investigate this, we will monitor the reaction of the immune system of current and ex oncological and haematological patients on the different COVID-19 vaccines (Pfizer, Moderna, AstraZeneca, Janssen Pharmaceutica). The adverse effects as a reaction on vaccination will be investigated in this population as well. Clinical data of the patients will be collected and a blood drawn will be performed at different time points: before vaccination and 4, 6 and 12 months after receiving the first vaccination dose. The blood samples will be used to determine the amount and efficacy of the antibodies against SARS-CoV-2. Patients will also be asked to report side effects after vaccination. This will be done with a questionnaire that will be sent to the patients three days after each vaccination. The primary endpoint of the study is the quantification of different anti SARS-CoV-2 specific IgG antibodies per study cohort at 4 months after the first vaccination. Depending on the availability, antibody titers will be quantified using a MULTIPLEX SARS-CoV-2 Immunoassay, Siemens Healthineers Atellica IM SARS-CoV-2 IgG (sCOVG) assay or an in-house developed anti-RBD ELISA (Sciensano). The secondary endpoints of the study are to investigate the evolution and duration of the immune response after vaccination in the patient cohort using serological assays to analyse anti-RBD IgG titers 12 months after the first vaccination. Another secondary endpoint is to analyse the titers of neutralizing antibodies both 4,6 and 12 months after receiving the first vaccination dose. Furthermore, it is aimed to investigate the efficacy of the immune response in the patient cohort for each different vaccine. This will be assessed by the SARS-CoV-2 infection rate based on information collected through questionnaires on incidence of (PCR-confirmed or chest CT scan confirmed) SARS-CoV-2 infection within a time frame of 12 months after the start of the study. At last, we will investigate the safety of the different COVID-19 vaccines that are commercially available in Belgium. Safety will be reported in terms of incidence and severity of adverse effects (AEs) using a questionnaire which will be sent via REDCap. Patients will be asked to enter their adverse events over a period of 3 days after the vaccination day. If the patient does not have an email address, the questionnaire can be completed on paper. Only patients who had their baseline visit prior to their vaccination will be asked to complete these questionnaires. To end, serious vaccine-related adverse events which lead to hospitalization or further examination will be reported in the eCRF. This research project will provide knowledge on how the immune reaction after vaccination develops in cancer patients and patients with oncological or haematological history.

Researcher(s)

• Promoter: Peeters Marc

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Advances in artificial intelligence (AI) have facilitated the development of solutions for numerous industrial, academic, and research challenges. We have developed a software, named Organoid Brightfield Identification-based Therapy Screening (OrBITS), for image-based analysis of 2D and 3D cancer cell cultures using computer vision technology combined with a convolutional network, machine learning approach (priority patents filed). As such, our OrBITS software can provide 2 major services: 1) software as a service for image-based research analysis and 2) high-throughput screening of therapeutic compounds. The technology and services are already of high interest to both industrial and academic partners, and we have begun performing image analysis and drug screening services for both internal and external groups. However, in order to facilitate and expand our service capacity, some technological and operational gaps must be met. Notably, we require dedicated personnel to perform drug screening of compounds provided by the clients, conduct routine maintenance of biological cultures, and integrate our current workflow with recently acquired state-of-the-art equipment (e.g. Tecan Spark Cyto live imager, Tecan D300e drug printer, Opentron OT-2 pipetting robot). The documentation and standardization of this workflow will streamline future expansion and increase service capacity. Furthermore, we aim to migrate our software to a cloud-based system to centralize data storage and training of the software AI network. Setting up this cloud system will resolve many issues associated with image-based analysis (e.g. inadequate data storage and traffic, inefficient and incremental software updates, absent data sets), which are described by our industrial and academic collaborators. Setting up this cloud-based system will further allow our AI software training unit to stay up-to-date and relevant with the fast past of scientific and translational research, thus keeping our image-based analysis and drug screening services at the cutting edge. Lastly, we aim to work with a dedicated business developer to perform market analysis, optimize pricing and advertisement strategies, and develop a business plan for our service platform, as currently we are working on a collaborative (case-by-case) modality. The technology and business development aims proposed here will enable the establishment of the OrBITS Platform to become a self-sustaining service provider with the ability to scale as the clients and needs increase.

Researcher(s)

• Promoter: Deben Christophe
• Co-promoter: Lin Abraham

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer is one of the most frequent malignancy worldwide and is an important contributor to cancer related deaths. The standard first-line therapy for patients with metastatic colorectal cancer (mCRC) is a cytotoxic doublet combined with targeted therapy (anti-EGFR). Sadly, not all patients show good responses to this therapy. RAS mutational status is a known predictive biomarker for response to anti-EGFR therapy. However, even in the group of RAS WT patients, the response rate to anti-EGFR therapy is only 30-50%, indicating that there are more resistance mechanisms to be discovered. In this project, we will study primary resistance mechanisms in RAS WT mCRC patients that do not respond to anti-EGFR therapy in order to identify new predictive biomarkers. New biomarkers to predict resistance are much needed as they could spare patients from unwanted side effects from ineffective therapies, enhancing efficacy and contributing to a better quality of life. Epigenetic changes in cancer have attracted great attention in recent years. Breakthrough research of our group has shown that certain methylation patterns can be used as biomarkers in a variety of cancer types, including colorectal cancer. Sparse data even indicates that certain methylation patterns can be responsible for the variability of therapeutic responses to anti-EGFR therapy in mCRC, but this is vastly underexplored. In this project, we aim to identify new methylation biomarkers for primary resistance to anti-EGFR therapy in mCRC using methylome data. The outcome of this study could have a major impact on patient treatment.

Researcher(s)

• Promoter: Op de Beeck Ken

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer immunotherapy strategies leave room for improvement. Given that a 'one-size-fits-all' approach is not the solution due to tumor heterogeneity, personalized therapy is the way forward. It is my mission to overcome hard-to-treat solid tumors and to push boundaries in achieving effective personalized immunotherapies. To accomplish this, the immunosuppressive nature of the tumor microenvironment needs to be overcome, allowing to significantly reduce its hampering effect on the activation and the infiltration of immune cells in tumors. My team recently demonstrated the power of certain activated immune cells to kill both cancer cells and cells of the tumor microenvironment that contribute to immunosuppression. With a view to further enhance antitumor effects, me and my team will unravel different inhibitory mechanisms that hamper antitumor immune cell responses and use these new insights to develop effective and personalized therapies that combine direct activation of immune cells with inhibition of immunosuppression. In the current 2-year project, we will gather novel tumor immunology data on 1) characterization of the tumor microenvironment, 2) interactions between tumor cells and immune cells, 3) relevant targeted treatment strategies and 4) biomarker identification; as important proofs-of-concept to further strengthen my European and consortium project applications in the near future.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Bogaerts Annemie

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing and usually fatal disease with a 5-year overall survival rate of less than 8%. Despite significant advances in understanding the molecular disease pathways and treatment of cancer, predicting individual responses to both standard of care and targeted therapies remains a stumbling block. The recent introduction of patient-derived tumor organoids as more physiological relevant models has revolutionized both basic and translational cancer research. However, current readouts to study these multicellular constructs only provide limited information. Considering the limitations described above, I aim to develop an innovative and more physiological relevant predictive co-culture platform that implements the effects of cancer associated fibroblast (CAFs) and hypoxia on treatment response. By using these state-of-the-art high-throughput multiplex endpoint and real-time live-cell imaging assays, I will screen a broad range of rationally designed combination strategies. Through this approach, I aim to unravel more effective and personalized combination strategies for pancreatic cancer. Eventually, I will also associate treatment sensitivity of the most promising combinations with gene mutation and expression signatures to identify novel predictive biomarkers for our innovative combination strategies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Deben Christophe
• Fellow: Le Compte Maxim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, and advanced HNSCC patients often experience relapse or metastasis (R/M HNSCC) resulting in dismal prognoses. These patients receive immunotherapy (ICI) alone or in combination with platinum-based chemotherapeutics (PLAT) as first-line treatment. While these combination treatments have some clinical benefit, they are limited by low response rates and severe side effects in already weakened patients. To address this, I will investigate a novel combination strategy with non-thermal plasma (NTP). NTP, an ionised gas, is a localised therapy that induces immunogenic cancer cell death (ICD), which can activate the patient's anti-cancer immunity. To date, no adverse side effects have been reported with the clinical use of NTP. Therefore, we hypothesize that combining NTP with PLAT/ICI will be well-tolerated and improve clinical efficacy in R/M HNSCC. In this project, I will perform 3D in vitro experiments on cell lines and primary patient material, and two mouse models will be used to validate the safety and clinical efficacy of this combination strategy. The successful completion of my project will help integrate NTP into current first-line therapies of R/M HNSCC as a new combination strategy to improve treatment efficacy and quality of life for those patients. This study will also be a stepping stone towards a broader implementation of NTP technology in other cancer types.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Bogaerts Annemie
• Co-promoter: Laukens Kris
• Co-promoter: Lin Abraham
• Fellow: Verswyvel Hanne

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic cancer is one of the most lethal cancer types worldwide, with barely a quarter of the patients still alive one year after diagnosis and a 5-year overall survival below 10%. This dismal outcome is mainly due to its high resistance to all current therapies. Therefore, innovative and effective treatment options are urgently needed for these patients. The tumor microenvironment is stated as the major confounding factor involved in therapy failure. This tumor microenvironment acts as a dense fibrotic shield around the pancreatic cancer cells and additionally creates an immune suppressive environment. Therefore, combination therapies that target both cancer cells and modulate this immune suppressive tumor microenvironment are the next-generation strategies. Hence, in this project I will first modulate the fibrotic shield by using ormeloxifene. This compound is included in the list for drug repurposing in oncology, underlining the fastest and most cost-effective way towards clinical application. Subsequently, I will reinforce the patient's own immune system to eliminate pancreatic cancer cells by exploiting next-generation inhibitory immune checkpoints. With this rationally designed combination, I aim to provide a solid, scientific rationale to initiate a novel clinical trial for pancreatic cancer patients who are in dire need for new treatments options.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc
• Co-promoter: Roeyen Geert
• Fellow: Quatannens Delphine

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) patients, especially those with advanced disease, are urgently in need of new treatment options that can increase their survival rate and quality of life. A promising strategy is immunotherapy, however, only a minority of patients responds to it because the cancer has developed mechanisms that evade its effects. In recent years, the RANKL/RANK signaling pathway has been implicated as one such mechanism, as it allows many cancer types - including CC - to circumvent the immune response by disrupting the communication of the immune cells. Supported by our first results, we strongly believe that blocking the RANKL/RANK signal can release the brakes on the immune system and reinvigorate the tumor's susceptibility to immunotherapy. We therefore aim to expose the best possible immunotherapeutic partner(s) for anti-RANK(L) therapy in order to achieve the most optimal anti-tumor immune effects. For this, we have unique access to CC samples retrieved from patients before and after anti-RANKL monotherapy, which we will thoroughly investigate to reveal immune related changes. Thereafter, we will perform additional laboratory tests that will allow us to pinpoint one best-in-class anti-RANKL combination strategy, which we will further optimize in CC mouse models. Finally, this project will validate a novel imaging technique to stratify patients and monitor treatment response for this therapy, thereby minimizing treatment - and economic burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Van den Wyngaert Tim
• Fellow: Verhoeven Yannick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide and is ranked second in terms of mortality (1). Nowadays, the gold standards for screening, diagnosis and follow-up of CRC all have important drawbacks. In light of these limitations, there is a need for new, non-invasive and accurate techniques. During the last years, liquid biopsies have been intensively studied as a potential novel method for the screening, detection and follow-up of CRC. Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or blood, are sampled and analyzed. Liquid biopsies of peripheral blood, for example, are used for the detection of circulating tumor DNA (ctDNA). This DNA originates from a tumor as a result of apoptosis and necrosis of cancer cells, thereby releasing their DNA into the bloodstream. CtDNA liquid biopsies are suitable for diagnosis as ctDNA can even be detected in the plasma of early-stage cancer patients. Analysis of ctDNA in CRC patients has already been studied. However, until now, a strong focus existed on the detection of tumor specific mutations, which has important limitations. We have strong published and preliminary data showing that specific epigenetic alterations can be used as universal biomarkers in different types of cancers. We aim to further characterize these epigenetic signatures in colorectal adenoma and carcinoma. Preliminary data of our research group has shown that methylation of GSDME, a known tumor suppressor gene, is a potential detection marker for CRC (2). Furthermore, we have demonstrated that NPY methylation in ctDNA is a good marker for total tumor burden and can be used for the follow-up of metastatic CRC patients (3). Therefore, in this project, we will develop a novel digital droplet PCR assay for liquid biopsies (plasma samples) that can detect GSDME methylation in ctDNA. We will study GSDME methylation in patients with CRC, colon adenomas and healthy subjects to determine whether this test can be used for CRC detection and screening. After we have validated this GSDME assay for CRC, we will conduct a prospective multicenter trial investigating the use of both GSDME and NPY methylation analysis in liquid biopsies to guide treatment in metastatic CRC. We will investigate whether liquid biopsies have the ability to detect progressive disease earlier than standard follow-up based on CT-imaging and whether adapting treatment based on liquid biopsies can improve progression free survival.

Researcher(s)

• Promoter: Peeters Marc

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing and usually fatal disease with a 5-year overall survival rate of less than 8%. Despite significant advances in understanding the molecular disease pathways and treatment of cancer, predicting individual responses to both standard of care and targeted therapies remains a stumbling block. This limited response rate is a result of the heterogeneity combined with an inadequate understanding of the complexity of the tumor microenvironment of PDAC. Therefore, tremendous efforts have been made in developing more physiologically relevant in vitro models that can accurately predict clinical outcome. Even though two-dimensional (2D) in vitro cancer cell lines have been widely used to unravel the molecular mechanism of tumor growth, these models are not able to mimic the in vivo complexity of PDAC. Patient-derived organoids on the other hand represent a more physiologically relevant model because they preserve the cellular heterogeneity and morphology of the primary tumor tissue. However, current readouts to study these multicellular constructs only provide limited information. Considering the major hurdles described above, we aim to develop an innovative and more physiological relevant predictive platform that implements the effects of cancer associated fibroblast (CAFs) and hypoxia on treatment response. By using these state-of-the-art high-throughput multiplex endpoint and real-time live-cell imaging assays we will screen a broad range of rationally designed combination strategies. Through this approach, we aim to unravel more effective and personalized combination strategies for pancreatic cancer. Eventually, we will also associate treatment sensitivity of the most promising combinations with gene mutation and expression signatures to identify novel predictive biomarkers for our innovative combination strategies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Deben Christophe
• Fellow: Le Compte Maxim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. In our search for new anticancer therapies, we discovered that Auranofin, an old drug currently used for rheumatoid arthritis, is highly effective against mutant p53 expressing cancer cells. P53 is the most frequently mutated gene in lung cancer and is often associated with an unfavorable therapeutic outcome. Auranofin is a selective inhibitor of the antioxidant thioredoxin reductase. Previous studies have shown that Auranofin dependent inhibition of this antioxidant blocks several pro-tumorigenic pathways. Recent findings have shown that these pathways are also involved in attracting immunosuppressive cells to the tumor microenvironment and in hiding cancer cells from immune cells. To date, little is known about the underlying mechanisms by which AF induces cancer cell death and if Auranofin can modulate the immune suppressive tumor microenvironment. In this strategic basic research project, we recently discovered that Auranofin induces different types of immunogenic cell death pathways, including the type of cellular 'rust' ferroptosis, which can stimulate the patient's immune cells to efficiently eliminate lung cancer cells. In addition, we will study the in vivo effect of Auranofin on different types of immune cells inside the tumor and peripheral blood to determine if Auranofin is a potential candidate for combination strategies with immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is a hematological cancer that arises and spreads from the bone marrow. It has a very dismal prognosis, characterized by a high relapse rate, despite initial complete molecular remission. Residual leukemic stem cells (LSC) are believed to be to origin of this relapse. LSC reside in a tumoral bone marrow that features a heightened state of hypoxia. Immunotherapeutic strategies are on the rise and are promising approaches to go hunt-and-destroy LSC. However, they will have to overcome the hypoxic burden in the leukemic bone marrow. Indeed, hypoxia is nowadays recognized as a barrier for immunotherapy. In this project, we will focus on natural killer (NK) cells as a born killer with great potential as adoptive cell product. While cytokines and chimeric antigen receptors (CAR) have improved the cytotoxic potency and targetability of NK cell products, their effectiveness at the tumor site is incapacitated by hypoxia. To address this conundrum, we will investigate several approaches to metabolically sustain their killing capacity in hypoxia in order to elicit potent elimination of both LSC and differentiated AML cells in the leukemic bone marrow. This will open up opportunities to develop next-generation CAR NK cells as an available off-the-shelf product for the treatment of AML patients.

Researcher(s)

• Promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

COVID-19 is a disease caused by an infectious outbreak of the SARS-CoV-2 virus. Today, the virus is widely spread throughout the world and declared by the World Health Organisation (WHO) as a pandemic. There are a broad range of clinical presentations of a SARS-CoV-2 viral infection varying from asymptomatic, sensation of a mild cold or flu to severe bilateral pneumonia and death. The mortality is the highest in the elderly and in people with a pre-existing condition such as cancer. In addition, it has already been shown that in patients with a severe COVID-19 infection the cytokine levels in the blood are very high, which can lead to organ failure. Since in cancer patients cytokine production is already increased by their disease and by treatment, this implies a higher susceptibility to develop severe COVID-19 when an exaggerated immune response to this virus produces even more cytokines ("cytokine storm"). The aim of this project is to be able to detect preventively when there is a risk of developing a "cytokine storm" so that potential therapy such as cytokine inhibitors can be used. To accomplish this, the response of the immune system to SARS-Cov2 infection will be mapped in this project. This will be done by performing immunological tests on blood samples from cancer patients and a healthcare workers the same oncology units who seropositive for the SARS-CoV-2 infection. Both blood samples from symptomatic and asymptomatic COVID-19 subjects will be examined immunologically. The immunological tests include immunoassays, flow cytometry and immunomethylomics. The collection of blood samples has already started at the end of March 2020 and the inclusion period is 3 months, so that the early phase, the peak phase and the foreseen decline of the pandemic are included. Cancer patients are asked to take additional blood samples during routine blood samples. A monthly blood sample is requested from the group of healthcare workers (4 samples per participant). First of all, the seropositive samples will be detected on the basis of a serological test. These results also provide insight into the proportion of infected high-risk patients in a hospital environment. On the basis of the immunological tests, the immune response will be compared between the symptomatic cancer patients and asymptomatic cancer patients and matched controlled healthcare workers. In this way, immunological risk factors for the development of severe COVID-19 can be identified and a new outbreak can be controlled in a scientifically responsible manner.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Huizing Manon
• Co-promoter: Peeters Marc
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Vulsteke Christof

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

SARS-CoV-2 is a respiratory virus making the lungs the primary site of infection. However, little is currently known about the interaction between SARS-CoV-2 and lung cancer cells. SARS-CoV-2 needs certain proteins on the host cell to recognize and infect them. If more of these proteins are present, it may mean that these cells are more easily infected by the virus. The aim of this study is to investigate the presence of these proteins on patients' cancer cells to determine whether lung cancer cells express these proteins more than normal lung cells and can therefore be infected by SARS-CoV-2. The second aim of this study is to investigate how cancer treatments used as standard for lung cancer patients (chemotherapy, targeted and immunotherapy) influence the expression of these proteins. We will check this on patient samples, but also in the lab on cancer and normal lung organoids. These organoids are directly derived from lung cancer patients and can be considered a patient in the lab who very well retain the characteristics of the original tissue. Using advanced equipment, we can quickly check the expression of SARS-CoV-2 related proteins after treatment with 15 different therapies. This study can therefore quickly provide us with more information about how anti-cancer treatments can influence the course of SARS-CoV-2 infections.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Currently we do not know well which complications occur that lead to death in COVID-19 patients and what changes occur in the different organs in case of a SARS-CoV-2 infection. In this study we answer these questions. We do this as follows: If a hospitalized COVID-19 patient dies, after consent from the legal representative, we perform postmortem a whole-body CT scan and subsequently obtain with a needle trough the skin pieces of tissue from heart, lungs, liver, spleen, kidneys and abdominal fat. Also we take blood. These materials are send to different laboratories for further studies. From the medical record, we collect relevant clinical data. These data, combined with the CT-scan results and results from the tissue examinations are the basis to establish the cause of death and contributing conditions during a deliberation of doctors from various specialties. Moreover, more detailed studies are being done on the tissues and the blood to study the interaction between the virus, the immune system and the tissues. Lastly, the unused tissue pieces are being stored in a biobank for future studies. This study will directly impact the care of hospitalized COVID-19 patients by revealing treatable or preventable complications of COVID-19 e.g. venous thrombosis or fungal infections. Also, it will inform us on potential targets for (preventive) treatment by exposing how SARS-CoV-2 damages the tissues and what are the main actors causing this damage.

Researcher(s)

• Promoter: Lammens Martin

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite the many scientific successes in ameliorating the outcome for cancer patients, cancer still remains the second leading cause of death worldwide, with about 1 in 6 deaths due to cancer. Therefore, we still have a long and difficult road ahead in finding new and improved cancer therapeutics. A major gamechanger in the treatment of cancer patients is the breakthrough of immunotherapy. Especially the introduction of immune checkpoint inhibitors resulted in significant increased overall response rates for several cancer types. However, despite their success, several disadvantages and hurdles to further improve the outcome of cancer patients are still present. Therefore, other strategies of cancer immunotherapy need to be explored to overcome or circumvent these drawbacks. Two promising approaches are currently in the scoop of cancer immunotherapy research, being (i) the use of natural killer cells to fight tumour cells and (ii) turning cold immunogenic tumours into hot immunogenic tumours. We have shown in our lab that natural killer cells can play a significant role in a cold immunogenic tumour like pancreatic ductal adenocarcinoma (PDAC). More specifically, after stimulation with interleukin(IL)-15, natural killer cells are able to not only kill the tumour cells but also the surrounding immunosuppressive stromal cells of the tumour microenvironment. Furthermore, we also demonstrated that the anti-tumour potential of IL-15 is significantly enhanced combined with an immunotherapeutic agent that works on antigen presenting cells. With the results of this project, we aim to initiate a first-in-human clinical trial with our combination immunotherapy. Patients suffering from various tumour types, including some which are not responding to standard chemo-/radiotherapy or current immune checkpoint inhibitors, could potentially have a better treatment outcome in the future.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Fusion genes are identified as clinically relevant drivers in non-small cell lung cancer (NSCLC), but emerging evidence shows these are present and are becoming clinically actionable in other cancer types as well. Therefore, the consortium consisting of CORE (UA) and Biocartis will study the potential of the Idylla™ GeneFusion Assay to detect gene fusions (ALK, ROS1, RET, and NTRK1-3) in other cancer types beyond NSCLC. Specifically, research will mostly focus on NTRK1-2-3 fusions, which have gained high clinical interest due to recent approval of the NTRK inhibitor larotrectinib for NTRK fusion positive cancers regardless of cancer type. Therefore, studies will be conducted in MSI-High colorectal cancer (MSI-H CRC), glioblastoma multiforme (GBM), (papillary) thyroid carcinoma ((P)TC) and melanoma, which have been shown contain kinase gene fusions and hence represent an ideal set of clinically relevant cancer types to study gene fusions. The IdyllaTM GeneFusion Assay can generically detect gene fusions irrespective of the fusion partner. However, in order to properly detect these kinase gene expression imbalances, knowledge on the baseline expression levels of kinases in different cancer types will need to be gained. Once this is determined, clinical sensitivity and specificity of the IdyllaTM GeneFusion Assay for each kinase in different cancer types will be determined by comparing the results of the IdyllaTM assay to the results of routine diagnostic tests, as well as to the ArcherDX® FusionPlex Lung Panel assay as an unbiased independent reference method. Another part of the research project will focus on maximizing the compatibility of the IdyllaTM GeneFusion Assay with cytological samples, which are increasingly used for diagnostics due to advances in minimally invasive sampling procedures. The research will study the effect of different pre-analytical variables in the cytological sample preparation workflow on the quantity and quality of RNA, which is essential for any downstream RNA-based test to be successful. Based on a literature review and an extensive questionnaire taken by Biocartis, several key variables were identified, e.g. sample transport conditions, type of fixative, sample type (smear or cell block), etc, which will be systematically studied using mimicked cytological samples (cell culture material) to identify 1 optimal workflow for RNA-based testing that is feasible to implement in routine clinical practice. Finally, a series of NSCLC cytological samples prepared using this optimal workflow will be prospectively collected to confirm clinical performance, i.e. low invalid rate and high sensitivity and specificity of the Idylla™ GeneFusion Assay on this prospective cohort of NSCLC cytological samples. Finally, snap frozen samples will also be studied since these are yet another sample type that, due to instant freezing without fixation after biopsy sampling, will yield very high RNA quality and quantity, thus representing a 'best-case' scenario to illustrate the potential of RNA-based testing in a clinical setting. While most routine diagnostic test samples will be FFPE, some clinical centres in fact have validated workflows for routine testing of snap frozen samples. Therefore, snap frozen NSCLC tissue samples will be tested using the Idylla™ GeneFusion Assay to demonstrate technical compatibility and to evaluate the degree of similarity between typical FFPE and cytological sample-derived NSCLC mRNA expression profiles.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite the discovery of new therapeutic strategies, lung cancer still accounted for more than 18% of the cancer-related deaths in 2018. P53 is the most frequently mutated gene in lung cancer and is often associated with an unfavorable therapeutic outcome. In our search for new anticancer therapies, we discovered that Auranofin (AF), an old drug currently used for rheumatoid arthritis, is highly effective against mutant p53 expressing cancer cells. The drug is a selective inhibitor of the antioxidant thioredoxin reductase. Previous studies have shown that AF dependent inhibition of this antioxidant blocks several pro-tumorigenic pathways. Recent findings have shown that these pathways are also involved in attracting immunosuppressive cells to the tumor microenvironment and in hiding cancer cells from immune cells. To date, little is known about the underlying mechanisms by which AF induces cancer cell death and if AF can modulate the immune suppressive tumor microenvironment. We hypothesize that AF can induce immunogenic cell death, a type of cell death that alerts the patient's immune system leading to an antitumor immune response. In addition, we will study the in vivo effect of AF on different types of immune cells inside the tumor to determine if AF is a potential candidate for combination strategies with immunotherapy.

Researcher(s)

• Promoter: Deben Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of only 5%. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are needed in order to prolong survival of MPM patients. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also, anti-PD-L1 immunotherapy has been approved for treatment of different cancers. Two clinical trials, investigating programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1) inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Smart combination strategies with other compounds might even improve the anti-tumor response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. Tumor-induced immune suppression might also be tackled by targeting the vascular endothelial growth (VEGF) / vascular endothelial growth factor receptor (VEGFR) pathway, which induces tumor growth in MPM. In this research project tumor-induced immunosuppression will be tackled via two different pathways: immune checkpoint blockade will be used to reactivate silenced anti-tumor immune responses while blockade of the VEGF/VEGFR signaling pathway will be used to target the tumor vasculature in order to reduce angiogenesis thereby reducing tumor growth. Our preclinical study aims to investigate a possible synergy of a combination strategy with immune checkpoint blockade and an anti-angiogenic compound. Preclinical proof-of-concept that our investigated combination strategies have got anti-tumor effects will guide the rational design of future clinical studies. The new insights delivered by our preclinical study will contribute to saving considerable time and money in the clinical phase.

Researcher(s)

• Promoter: Marcq Elly

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In general, when a patient is diagnosed with invasive breast cancer the amplification status of the HER2 gene is evaluated by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH) on the primary tumor. International literature demonstrates that in 7-20% of cases HER2 heterogeneity takes place, especially between the primary tumor and bone metastasis. Furthermore, heterogeneity in time can occur due to treatment selection. Although reports have demonstrated that heterogeneity of the HER2 status at different sites occurs, only seldom new biopsies are analyzed to re-evaluate the HER2 status. By liquid biopsy, we can overcome this issue as liquid biopsies can (more) easily be repeated over time and contains cell-free tumor DNA (ctDNA) from the whole tumor mass. Hence this research can lead to a more detailed analysis of the presence of heterogeneity of HER2 amplification in this patient group. With this project, we plan to develop an assay that can accurately detect HER2 amplification in a liquid biopsy of breast cancer patients. Furthermore, we will investigate HER2 heterogeneity in breast cancer patients who progress upon first-line treatment (such as hormone therapy). By analysis of a liquid biopsy upon progression to first-line therapy in patients without HER2 amplification (at diagnosis on primary tissue biopsy), we expect to identify the patient group in which the HER2 amplification status has changed (significantly) and might benefit from anti-HER2 therapy. The innovative aspect of this project is that we will evaluate HER2 amplification (by ddPCR) in both the blood and urine simultaneously. Whereas blood sampling is minimally invasive, urine sampling is non-invasive and can easily be repeated over time. We will combine the HER2 amplification data with the results of a methylation assay (ddPCR) or the results of other frequent occurring gene aberrations (AVENIO ctDNA) to know whether enough tumor DNA is present in the circulation/urine for reliable analysis. Currently knowledge on the presence of ctDNA in the cfDNA fraction is lacking in many liquid biopsy studies. As long as we have no idea on the presence of ctDNA in our sample, we cannot distinguish a negative result from a non-informative result due to low ctDNA content by liquid biopsy. The overall aim of this project is to evaluate the discrepancies of HER2 amplification status between primary tumor and metastatic lesions that develop during therapy. To meet this objective we will pursue following aims: - Develop and evaluate an assay to measure HER2 amplification in the blood and urine by ddPCR. - Develop and evaluate a methylation assay to estimate the amount of cfDNA derived from tumor cells present in the blood and urine by ddPCR. - Evaluate an NGS assay detecting multiple breast-specific gene aberrations in the cfDNA from blood (AVENIO ctDNA assay). - Evaluate HER2 amplification in patients without a FISH positive HER2 status of the primary tumor who develop multiple organ metastasis during therapy.

Researcher(s)

• Promoter: Pauwels Patrick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Today, most cancers are diagnosed through tactile lesions, imaging techniques, or clinical symptoms. This diagnosis is confirmed by a histopathological examination of a core biopsy of the primary lesion. However, a biopsy is very invasive, quite difficult to obtain and causes great discomfort to the patient. Because tissue (re) biopsy is often a problem, the use of liquid biopsies has become extremely popular in recent years. While the detection of diagnostic, prognostic and predictive biomarkers is generally performed on tissue samples, detection on liquid biopsies shows promise. Currently, liquid biopsy analysis is mainly focused on plasma testing. Compared to tissue tests, blood tests are minimally invasive. While a blood sample is considered minimally invasive, a skilled caregiver is required to draw blood from patients. In addition, the patient's health status may not allow for additional blood draws. Obtaining urine, on the other hand, is non-invasive, does not depend on the health status of the patient, is without limitation on volume or frequency of collection, and can be performed at home or at the physician's office. There is a huge variety of biomarkers in liquid biopsies, including circulating tumor cells (CTCs), cell free nucleic acids (cfNA), exosomes and proteins that show promise for non-invasive testing. Depending on the type of molecule, different "omic" technologies (i.e. genomics, transcriptomics, proteomics and metabolomics) are used to detect them. Realizing the potential of urine as a liquid biopsy requires research into optimal collection methods and storage conditions for the detection of biomarkers. Colli-Pee® was developed by Novosanis and allows to collect urine in a standardized and volumetric way. If collection methods and storage conditions can be standardized, yellow can become the new red and urine can replace or equate blood in cancer detection.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Zwaenepoel Karen
• Fellow: Jordaens Stephanie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Natural killer (NK) cells are potent cytotoxic cells from the hematopoietic system, playing an important role in the control of infection and malignancy. NK cells often operate under harsh conditions, such as in deprived oxygen or hypoxia. Hypoxia stabilizes its primary regulators hypoxia-inducible factors (HIF), more specifically HIF-1? and HIF-2?. While hypoxia reduces NK cell-mediated cytotoxicity, data on other NK cell features is conflicting. In addition, the role of HIF in NK cells has been neglected, as only one mouse study demonstrated that HIF-1? ablation in NK cells indirectly reduces tumor load via angiogenic rather than cytotoxic effects. However, murine NK cells show quite some disparities to human NK cells. In addition to hypoxia, also stimuli such as cytokines can stabilize HIF. Hence, HIF could play a pivotal role in NK cells. Therefore, this project aims to gain fundamental insights in the role and regulation of HIF in human NK cells via combining omics with functional assays. First, we will unravel the effect of hypoxia on (stimulated) NK cells. Next, we will dissect the divergent roles of HIF-1? and HIF-2? in the functioning of NK cells in response to hypoxic and stimulatory conditions. HIF isoform-specific knockout NK cells will be created using CRISPR-Cas9. Finally, we will elucidate how HIF isoforms regulate their effects in NK cells. The obtained knowledge could prove extremely valuable in rational guidance of rising novel NK-cell based immunotherapies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer patients are at higher risk of developing COVID-19 and suffer a higher likelihood of poor disease outcome due to their underlying illness and/or therapy. Therefore, effective vaccination of cancer patients is of utmost importance. However, it is unclear if the immune system of cancer patients under active oncological treatment is able to mount an effective immune response. We aim to assess the development of protective immunity against COVID-19 upon vaccination in cancer patients.

Researcher(s)

• Promoter: Van Dam Peter

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) remains a leading cause of cancer related deaths in women worldwide. Over the last decades, little progress has been made in the systemic treatment of patients with advanced or recurrent forms. To successfully battle this cancer and improve long-term benefits for the patient, anti-cancer responses need to be stimulated whereby the immune system eradicates all residual cancer cells and prevents disease outbreak by anti-tumor immunity. Since CC has shown to be immunogenic, a promising hot field of research in oncology that opens new perspectives for its treatments is immunotherapy. However, tumor cells seem to have multiple mechanisms for evading immune surveillance, which is believed to be a major confounding factor involved in failure of currently used immunotherapies, like immune checkpoint inhibitors (ICI). In recent years, the RANKL/RANK signaling pathway has been implicated as a key player in this tumor-induced immunosuppression, making it a very attractive target to reinvigorate the tumor susceptibility to checkpoint inhibition. Signaling between receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) is best described for its obligate role in the differentiation of bone-resorbing osteoclasts and consequential bone-derived diseases, such as postmenopausal osteoporosis and cancer-related bone destruction. This has led to the development of denosumab, a fully human monoclonal antibody that binds RANKL, thereby blocking the interaction with its receptor, RANK. Recently however, it has been shown that RANK and RANKL are commonly highly co- expressed on tumor cells and immune cells in their tumor microenvironment (TME). Accumulating evidence highlights the pivotal role that RANK/L signaling has in allowing tumor cells to evade immune surveillance by modulating the tumor immune environment, and in participating in every step of cancer progression, given its pleiotropic effects on tumor cells and its microenvironment. The primary objective of the proposed research project is to expose the functional mechanisms of the RANK/L signaling pathway in CC. The second objective is to exploit the effects of denosumab on the migratory and invasive features of cervical cancer cells. We hypothesize that RANK/L signaling plays a key role in both the metastatic as immune modulating features of CC, and therefore we see great potential in investigating the drug repurposing of denosumab in the battle against this type of cancer.

Researcher(s)

• Promoter: Van Dam Peter

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Development of therapeutic resistance poses a challenging problem and limits the success of cancer therapies in the clinic. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is currently used for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) as well as recurrent/metastatic HNSCC. However, 5-year survival rates remain low. In this project, we will focus on the identification of novel combination therapies to overcome cetuximab resistance. Targets for the combination will be identified through genetic and proteomic analysis of the molecular profile of the tumour. We hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy combining (i) cetuximab with (ii) radiotherapy and (iii) an additional molecularly targeted agent, can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. We will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. The potential of these combination therapies will be investigated in vitro on a well-established, comprehensive panel of HNSCC cell lines with different sensitivities to cetuximab. Synergistic combinations will be validated under hypoxia and in 3D spheroids. Next, the most promising combination strategy will be investigated in vivo in HNSCC patient-derived xenograft (PDX) mouse models. The biological and therapeutic implications of our study hold great promise for clinical translation in patients with HNSCC.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic cancer (PDAC) is the 3th leading cause of cancer related death in the western world and the incidence is still rising. Due to its rapidly progressive nature and lack of early symptoms, 80-90% of the patients present itself late with advanced or metastatic disease. This results in the worst 5-year survival of all cancers (7%). Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine which has only modest improvements in survival due to chemoresistance in the majority of patients. The promising advantages that have been made in several cancer types are in great contrast with the scarce therapeutic improvements in PDAC. The tumour microenvironment (TME) is believed to be a major confounding factor involved in failure of conventional therapies, as well as in targeted and immune therapy. A hallmark of this microenvironment in PDAC is the strong desmoplastic reaction, orchestrated by the pancreatic stellate cells (PSC), which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC). This stroma, which can cover more than 50% of the tumour, consists of extracellular matrix, activated PSC and a variety of immune cells such as macrophages, T-lymphocytes, dendritic cells and natural killer cells. By acting as a mechanical and functional shield to the tumour, it plays a central role in the development, progression and invasion of PDAC and also creates an immunosuppressive TME by secretion of immunosuppressive factors. Therefore, we will attack PDAC on both fronts being the cancer cells and its surrounding stromal shield. To achieve this, we will investigate a novel, highly potent combination immunotherapy for PDAC, consisting of both immune stimulatory as well as anti-immune suppressive agents.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Bladder cancer has approximately 2300 new cases in Belgium every year (www.kankerregister.be). Especially in men, bladder cancer is common and is the fourth most common cancer in the world. Nevertheless, the diagnosis of bladder cancer is still not optimal due to the defects of the current standards of urinary cytology and cystoscopy. In addition, the necessary lifelong follow-up makes bladder cancer the most expensive cancer to be treated (Sievert et al., 2009). A non-invasive, cheaper and highly sensitive and specific biomarker set is therefore needed to optimize the diagnosis of bladder cancer on the one hand and to improve the follow-up of low-grade bladder cancer patients on the other. This will improve the quality of life of the patient and decrease the mortality of bladder cancer, the latter through good relapse monitoring, which reduces the risk of metastasis. Exosomes (30-120 nm) are extracellular vesicles (EVs) that are secreted into different body fluids and they contain both RNA, lipids and proteins. They end up in the urine because they are excreted by the epithelia of the urogenital tract. They have enormous diagnostic potential since they play a role in intracellular communication and tumor progression. During the PhD, a method for the purification and characterization of EVs was optimized (results published in JEV). A variant study was performed to determine the interindividual variation at EV protein level. This information has not been known so far, although it is imperative to establish a good discovery experiment capable of identifying an EV protein biomarkers for bladder cancer. The variant study shows that we have to include around 60 samples per experimental group. On the one hand, the urinary EV protein profile of bladder cancer patients will be compared with that of healthy individuals in order to obtain a diagnostic biomarker set. On the other hand, timelines will be established for bladder cancer patients from diagnosis to relapse. By comparing these time points, a biomarker set can be searched for the follow-up of bladder cancer patients. Finally, there will also be a validation study of the potential biomarker sets in a larger population, including patients with other bladder-related pathologies in collaboration with external partners (this validation study is not part of the doctoral work).

Researcher(s)

• Promoter: Mertens Inge

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The purpose of this translational research project is the development of a new combination immunotherapy for pancreatic cancer. We will focus on both activation of the immune system and at the same time inhibition of immune suppression. Importantly, not only the tumour cells themselves but also the pancreatic stellate cells which form a barrier around the tumour. by this unique focus, our innovative therapeutic approach has a higher chance of success.

Researcher(s)

• Promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5- year survival rate of only 5%. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are needed in order to prolong survival of MPM patients. Smart combination strategies might improve the anti-tumor response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. In this research project tumor-induced immunosuppression will be tackled via two different pathways: immune checkpoint blockade will be used to reactivate silenced anti-tumor immune responses while blockade of the VEGF/VEGFR signaling pathway will be used to target the tumor vasculature in order to reduce angiogenesis thereby reducing tumor growth. In addition, we are keen to assess the positive impact that exercise may have on these combination strategies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: van Meerbeeck Jan

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour, however it remains a rare disease (incidence: 3.20/100,000). Tumour progression is fast and recurrence inevitable. The added value of the current standard of care (SOC: surgical resection, radiation and chemotherapy) is only limited, leading to a median survival of less than 15 months and a five-year survival of less than 5%. In addition, undesired side effects impact on the quality of life. Hence, new effective treatment modalities represent a highly unmet need. While scientific advances have generated clinical breakthroughs in other cancer types, this has remained a standstill in GBM for nearly 15 years. Immunotherapy has generated remarkable clinical success in the past decade, in particular with immune checkpoint blockade (ICB). Recent preclinical evidence has suggested that combination therapy can render GBM sensitive to ICB. In this project, we will develop an immunometabolic therapy in murine GBM models in vivo as innovative treatment option. We hypothesize that our combination strategy will ameliorate clinical outcome while improving quality of life.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Specenier Pol

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In this project we aim to develop a novel combination therapy to treat cancer that combines induction of oxidative stress with immune checkpoint inhibition. By this project, we will obtain insight in the underlying mechanisms of ionized gas for cancer treatment by doing in vitro and in vivo experiments. We will investigate the effects of both direct and indirect treatment on pancreatic cancer and melanoma cells, in terms of: 1) induction of reactive species, 2) selectivity towards cancer cells versus normal cells, 3) effect of hypoxia; and 4) immunogenicity. Next, we will test the therapeutic effect of the combination of oxidative stress with immune checkpoint inhibition.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Quatannens Delphine

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Everolimus is a targeted therapy commonly used for patients with advanced pancreatic neuroendocrine tumors (PNETs). Unfortunately, after a while patients develop resistance, seen as progression on medical images. Earlier detection of resistance allows a quicker change to more effective therapies, results in better patient outcome, spares patients from ineffective treatment and reduces costs for society. Building on cell line data, fusion genes will first be studied in everolimus-naïve PNET patients as they may represent interesting genetic markers. For further experiments, tissue and monthly blood and urine samples from 30 PNET patients starting everolimus treatment will be collected (EVEREST trial). To identify the first resistance-predicting mutations, the DNA sequence of tumor tissue before and after everolimus-resistance will be compared. Next, we will study the possibility of detecting predictive mutations in non-invasively obtainable tumor DNA fragments in blood and urine (CtDNA) and of using serial CtDNA level measurements as a follow-up marker, both aiming at earlier detection of everolimus-resistance. CtDNA level is estimated by detection of tumor-specific mutations in serial plasma and urine samples. These mutations should be present at baseline and are selected based on the tumor's genetic profile, the experiment on fusion genes, previously obtained results and literature. We expect to detect a rise in CtDNA level when resistance develops.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: Boons Gitta

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The first aim of this study is to investigate the efficiency of three circulating cell-free DNA (cfDNA) stabilizing blood collection tubes at room temperature as well as at a lower temperature. The setup of this study will be similar to that of our comparison study of the centrifugation protocols. Blood samples from KRAS-mutated cancer patients will be collected. In addition to these three collection tubes, one blood sample will be collected in a standard EDTA tube, which will be used as a gold standard. We will perform digital droplet PCR (ddPCR) analysis, which is a highly sensitive technique designed to detect low abundant genetic aberrations. This will provide us with the absolute amount of KRAS mutated ctDNA as well as the allele frequency (AF). Furthermore, we will also perform a fragment analysis by quantitative, real-time PCR (qPCR). This will allow me to assess the cfDNA quality. Based on the results of these analyses, we will be able to select the most optimal cfDNA stabilizing blood collection tube. This will complete our work in providing an optimized liquid biopsy workflow for implementation in clinical practice. The second aim is to perform simultaneous cfDNA and cfRNA analysis of plasma samples from early stage PDAC patients to identify novel biomarkers. Blood samples of 19 PDAC patients are being collected prior to surgery and at specific time point after surgery. CfDNA analysis will also be performed by KRAS ddPCR. On the other hand, the cfRNA will be sequenced by Biogazelle, a company which specializes in RNA research. They will perform differential gene expression analysis (i.e. looking at differences of individual genes) as well as gene set enrichment analysis (i.e. looking at differences in sets of related genes). We will further analyze results with regards to described gene alterations in collaboration with the department of Pathology (UZA). Thorough statistical analysis will be performed to determine the influence of these results and the KRAS mutational status on the success of the surgery and survival of these patients. These results would not only significantly boost further research in the diagnosis and follow-up of PDAC patients, but would also provide novel insights in simultaneous cfDNA and cfRNA analysis.

Researcher(s)

• Promoter: Pauwels Patrick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

LC-MS/MS proteome analysis of insect tissues (samples) with gel-free methodology, including -prior to proteome analysis- cellular compartment fractionation of the total proteome and cell membrane proteome extraction with tube-gel technique. More specifically: • Proteome isolation will take place from 70 frozen insect tissues (samples) x 2 conditions per sample (soluble fraction, membrane bound faction) • Gel-free LC-MS/MS protocols will be employed on a high-resolution MS instrument. • Cellular fractionation of the total proteome will be done prior to the proteome analysis. • Tube-gel extraction of the membrane proteins will take place.

Researcher(s)

• Promoter: Mertens Inge

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer-associated fibroblasts (CAFs) provide a physical barrier for the delivery of systemic therapy to the tumor, making it an attractive target to combine with conventional treatment. Clinically addressing CAFs has been challenging due to its heterogeneous nature with both cancer-promoting and -restraining features. We have recently identified a distinct subset of CAFs in colorectal cancer specimens, marked by the expression of immune checkpoint CD70, and associated with a grim prognosis for the patient. Interestingly, CD70 is absent from normal epithelial tissue making it a safe target to eradicate the tumor-promoting CAFs. Therefore, the primary objective of the proposed translational research project is to develop a safe, effective cell-based strategy to eliminate CD70-positive cancer-associated fibroblasts. The secondary objective of the project is to rationally design and to preclinically evaluate a combination regimen of CD70-targeted therapy with first-line chemotherapy as a novel treatment option for patients with advanced CRC. Since we have also found CD70 expression in pancreatic cancer, this study can also pave the way to application in other malignancies.

Researcher(s)

• Promoter: Jacobs Julie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) retains its position as one of the most prevalent types of cancer with around 700,000 deaths per year worldwide. Treatments focused on altering the immune system have recently paved their way into oncology with clinical achievements seen in a broad spectrum of solid tumors. However, signals of activity in CRC are largely involving microsatellite instable tumors, leaving a great need for effective immunotherapy in the majority of patients. The biologica! complexity of the tumor microenvironment seems to be an obstacle for cancer immunotherapy, suggesting that a strategy to solely targeting tumor cells is inadequate to overwhelm the aggressively growing tumor in CRC. Cancer-associated fibroblasts (CAFs) represent the dominant constituents of the tumor stroma and play a critica! role in the proliferative and invasive behavior of CRC. Additionally, CAFs provide a physical barrier for the efficient delivery of systemic therapy to the tumor making it an attractive target to combine with conventional treatment. Clinically addressing CAFs has been challenging due to its heterogeneous nature with both cancer-promoting and cancer-restraining features. We have recently identified a phenotypically distinct subset of CAFs in invasive CRC specimens, marked by the expression of CD70, and associated with poor prognosis of the patient. Moreover, CD70-positive CAFs proved to stimulate tumor invasion and to promote immune escape by the accumulation of immune suppressive regulatory T-cells. lnterestingly, CD70 is totally absent from normal epithelial tissue making it a safe target to eradicate the tumor-promoting CAFs. Based on our preliminary data, we hypothesize that targeting CD70-positive CAFs in CRC has a potential triple mode of action by enhancing anti-tumor immunity, eradicating a permissive niche for tumor invasion and increasing the efficacy of first-line chemotherapeutics. The primary objective of the proposed project is to find the ideal approach to deplete CD70-positive CAFs. The second objective is to design a combination strategy of CD70-targeted therapy with a first-line chemotherapeutic agent that elicits a potent anti-tumor immune response. The third objective is to identify potential bloodbased biomarkers for diagnosis and to monitor treatment response. Experiments will be performed in vitro under normoxic and hypoxic conditions and in vivo in an orthotopic syngeneic mouse model to identify the ideal timing and dosing of our combination strategy. This translational research project wil! lead to the launch of a phase 1/11 clinical trial in patients with advanced CRC with a grim prognosis of only 12 to 14 months. Since we have also found CD70 expression in the desmoplastic stroma of pancreatic cancer, this study will also pave the way to application in one of the most therapeutically resistant maliçinancies.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Jacobs Julie
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Rolfo Christian
• Co-promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Both targeted therapies and immunotherapies are now at the forefront of personalized cancer medicine. Aberrant signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumorigenesis of multiple cancer types, making it a compelling drug target. In addition, it is well established that natural killer (NK) cells possess natural anti-tumour activity and can mediate antibody dependent cellular cytotoxicity (ADCC) upon binding with monoclonal antibodies, such as the EGFR inhibitor cetuximab. However, the presence of drug resistance and/or immune evasion is a major obstacle to progress in this field. In our project, we will concentrate specifically on head and neck squamous carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Center for Oncological Research (CORE) Antwerp. In this research project, we hypothesize that increasing the NK cell activity by cetuximab in combination with targeting NK cell immune checkpoint molecules can synergistically generate immune mediated elimination of HNSCC cells that are resistant to treatment with cetuximab alone. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. By characterizing NK cell functionality and, by extension, the whole immune checkpoint profile in HNSCC, we aim to rationally design new combination strategies to overcome cetuximab resistance, with the ultimate goal to improve the prognosis and life quality of HNSCC patients. Hereby, we will focus on HPV status and the hypoxic microenvironment as important mediators of treatment response. Therefore, the nature of our project is translational, as from the beginning, the link with clinical data is considered to be imperative before moving on to further preclinical investigation of the identified combination strategies. Successful combinations will be validated in animal studies, which will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the most promising combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel combination strategy, we are confident that the data generated in this project will favour the setup of a successful clinical trial with the newly identified combination regimen.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The host's laboratory's promising results of IL13 treatment in a mouse model for MS, encourage us to further investigate this potential therapeutic strategy in a human setup. Therefore, we propose to develop a human in vitro demyelination model to study the effect of IL13-induced M2 macrophages and microglia. We will do so by (I) differentiating hiPSC towards oligodendrocytes; (II) evaluating the myelinating potential by oligodendrocyte-neuron co-culture; (III) optimizing a toxin-induced demyelination procedure; and (IV) evaluating the effect of macrophage/microglia addition with or without IL13 stimulation.

Researcher(s)

• Promoter: Le Blon Debbie
• Co-promoter: Ponsaerts Peter

Research team(s)

• Laboratory for Experimental Hematology (LEH)
• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous, mostly professional, asbestos exposure in most afflicted patients. Although preventive measures to limit asbestos use and exposure have been around for several decades, the incidence of MPM is still expected to increase over the next decade due to the long latency between asbestos exposure and MPM development. The prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of less than 5%, due to its aggressive nature and the limited effectiveness of any conventional anti-cancer treatment (i.e. chemotherapy, surgery and radiotherapy). The new chemotherapy regimens consisting of a combination of a platinum compound and the folate antimetabolites pemetrexed or raltitrexed have a significant but limited impact on overall survival in MPM. Therefore, new therapeutic strategies are needed to complement the limited armamentarium against MPM. The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing research domain of cancer immunotherapy. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also anti-PD-L1 immunotherapy has been approved for treatment of different cancers. PD-1 and PD-L1 expression data in MPM of us and others laid the basis to evaluate their suitability as immunotherapeutic targets also in MPM. Two clinical trials, investigating PD-1 or PD-L1 inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Two other immune checkpoints, being lymphocyte activation gene-3 (LAG-3) and T-cell mucin immunoglobulin-3 (TIM-3), recently gained more interest since they have been described to be associated with T-cell tolerance and exhausted T cells that are infiltrating the tumor micro-environment. Our data on TIM-3 and LAG-3 expression in MPM effusions and on TIM-3 in MPM tissue samples identify both as promising new targets in MPM. Combined targeting of PD-1/PD-L1 with TIM-3 or LAG-3 was highly effective in controlling tumor growth in vivo in different other solid tumor models, providing a rationale to investigate combined blockade also in MPM. Smart combination strategies might improve the antitumor response by interfering with multiple immune escape mechanisms.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Marcq Elly

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC), accounting for an estimated 85% of all lung cancers, retains its position as the most lethal type of cancer worldwide, with a 5-year survival rate for newly diagnosed cases below 20%. Despite the remarkable progress that has been made in the development of new treatment modalities, chemotherapy consisting of platinum-based doublets remains the standard first-line treatment for NSCLC patients. Anti-mitotic drugs are well-established components of the current combination treatment schedules in NSCLC patients. Nevertheless, serious adverse effects remain the dose-limiting factor. New approaches target cardinal regulatory proteins of mitosis, with Polo-like kinase 1 (Plk1) as one of the most promising targets in this research field. Our previous research showed Plk1 overexpression in 65% of NSCLC patients while no or weak Plk1 expression was noted in normal lung tissue, making it a compelling target for the treatment of NSCLC. Volasertib, at present the lead agent in category of Plk1 inhibitors, has been shown to be highly effective in multiple carcinoma cell lines and xenograft models, with minimal toxicity in normal cells. However, only modest anti-tumour activity was reported for volasertib monotherapy in patients with solid tumours, including NSCLC. Remarkably, an encouraging percentage of these patients reaches stable disease, providing an intriguing window for improving patient outcome. Based on promising results of our recent preclinical research at the Center for Oncological Research (CORE, UA), this proposed project will focus on (i) the identification of predictive biomarkers for Plk1 inhibition; and (ii) novel, rationally designed combination strategies with Plk1 inhibitors to improve therapeutic benefit. We previously identified p53 and hypoxia as potential biomarkers for response to Plk1 inhibition. However, no conclusive evidence could be found yet. As such, in the first objective of the proposed study, we will gain conclusive insights in the predictive role of p53 and hypoxia for the response to Plk1 inhibition. Therefore, we will investigate the effect of Plk1 inhibitors in a panel of isogenic cell lines with a different p53 background, under both normoxic and hypoxic conditions. Our second objective is to identify promising combination strategies with Plk1-inhibitors. In this regard, we will especially focus on drugs that eliminate senescent cells upon Plk1 inhibition. Recently, preclinical research by us has identified cellular senescence as an important outcome of Plk1 inhibition. Senescent cells are irreversibly growth-arrested, but remain metabolically active, thereby secreting multiple tumour-promoting factors to adjacent tumour cells. In-depth evaluation of the molecular pathways involved in induction of senescence after Plk1 inhibition will lead to the identification of potential targets to kill senescent NSCLC cells after Plk1 inhibition. At the time of writing this application, no investigation has been performed yet on the molecular pathways important for the survival of senescent cells after treatment, making this project challenging yet essential to enhance anti-tumour responses after Plk1 inhibition. Lastly, our third objective is to evaluate a novel combination therapy of Plk1 inhibitors with agents eliminating senescent cancer cells, in both vitro and in vivo models of NSCLC. We hypothesize that the anti-cancer effect of Plk1 inhibitors is synergistic with agents eliminating senescent cancer cells, so that this innovative combination strategy will ultimately result in improved survival and quality of life for patients with NSCLC. The proposed research project has the exciting potential to create a breakthrough in the optimization of Plk1 inhibition for patients with advanced NSCLC. Moreover, since Plk1 overexpression is found in multiple tumour types, our study results might also pave the way for improved treatment options for other malignancies.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Lardon Filip
• Fellow: Domen Andreas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide and a marginally improving 5-year overall survival rate which remains below 20%. Successful therapeutic advances have emerged, but these treatment options are limited to only a small subset of NSCLC patients. Therefore, new treatment strategies are needed that will result in durable responses for the majority of NSCLC patients. In this regard, combining an immune modulatory chemotherapeutic agent with immunotherapy would be a suitable and promising approach. On the one hand, it has been shown that certain chemotherapeutics can induce immunogenic cell death, thereby releasing neoantigens and enabling tumor-specific cytotoxic T cell responses. On the other hand, CD70 has emerged as a promising target to be blocked in various hematological and solid malignancies. Its overexpression on tumor cells is associated with immune suppression in the tumor microenvironment. CD70 overexpression on NSCLC cells was detected by us in a subset of patients (16%). More importantly, preliminary findings from our group demonstrated the ability of certain chemotherapeutics to induce CD70 overexpression on NSCLC cells, which broadens the therapeutic window of anti-CD70 immunotherapy. Built on these preliminary findings, the primary aim of this study is to identify the ideal chemotherapeutic agent to combine with anti-CD70 immunotherapy by thoroughly evaluating several chemotherapeutics for their capacity to induce immunogenic cell death and stimulate CD70 overexpression on NSCLC cells. The second aim is to investigate the anti-tumor capacity of this treatment strategy together with the recently approved immune checkpoint inhibitor anti-programmed death (PD)-1, in order to develop an innovative approach that tackles the immunosuppressive factors of the tumor from different angles. Experiments will be performed in vitro in normoxic and hypoxic conditions and in vivo in a syngeneic mouse model. This project has the exciting potential to unravel a novel combination strategy for NSCLC patients that enables specific targeting of the tumor cells and realizes durable responses by stimulating the anti-tumor immune response. In addition, these study results might also pave the way for improved treatment options in other tumor types.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Jacobs Julie
• Co-promoter: Smits Evelien
• Fellow: Flieswasser Tal

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer metastases is responsible for 90% of the cancer related deaths. Due to an increased knowledge of the biology of cancer, more patients are referred to targeted therapy. The efficacy of these drugs depends on the molecular characteristics of the cancer cells. In addition, recent research has shown that molecular characteristics of cancer cells can change during cancer progression and metastasis. Since it is practically difficult to sample metastatic tissue repeatedly, investigating alternative matrices is imperative, paving the way for liquid biopsies. One possibility is to evaluate the molecular characteristics of circulating tumor cells, obtained from peripheral blood. However, before these cells can be used as matrix for molecular diagnostics, is should be evaluated if these CTCs have the same characteristics as the primary or metastatic tumor cells. In addition, due to heterogeneity in the primary tumor/metastases, is should be evaluated how many CTCs need to be analyzed in order to capture the dominant driving clones. In order to evaluate this, genomic changes from CTCs will be compared to the genomic composition of the primary tumor and the metastases. If successful, this project will allow a translation of liquid biopsies from the bench to the bedside, sparing patients from difficult and painful treatments.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Peeters Marc
• Fellow: Brouwer Aaltje

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

IBC is characterized by a rapid onset, redness and swelling of the breast. Despite an aggressive therapy with chemotherapeutics, radiation and surgery the survival rate is the worst among all breast cancers with less than 40 % survival after 5 years. Therefore, further research is necessary. Although IBC and non-IBC (nIBC) tumours are different diseases in many ways, our lab showed that genetically an IBC tumour and a nIBC tumour are not so different after all. Based on these findings we think that the non-cancerous cells that are part of the tumour or the patient's response to the tumour can explain the difference. Thus we are interested in how the surrounding tissue and especially the immune cells respond to IBC and how this is different from nIBC. To examine this we will start our research by determining what types of cells are present in both tumour types and whether they are functioning as they should be. By correlating the presence of certain cell types or functional markers with response to treatment, survival information and properties of the tumour we can see what type of cells or functional markers could predict prognosis or response to therapy and can be called biomarkers. Furthermore, the combination of this information with data about which genes in a tumour sample are over- or underexpressed could lead to a better understanding of the genetic pathways that are important in IBC growth. If we can alter these pathways, we might find new targets for therapy.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Colpaert Cecile
• Co-promoter: Trinh Xuan Bich
• Co-promoter: Van Laere Steven
• Fellow: Van Berckelaer Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

To study in a retrospective series of archival paraffin embedded cervical, CIN I, CIN III and invasive cervical cancer samples the relationship between RANK signaling, the immune infiltrate and targets for checkpoint inhibition. This should be the preliminary work for FWO or KotK grant application

Researcher(s)

• Promoter: Van Dam Peter

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite many efforts, non-small cell lung cancer (NSCLC) has a dismal 5-year survival rate of less than 20% due to frequently occurring therapy resistance. In addition, currently available targeted therapies are only applicable to limited subgroups of patients. The presence of TP53 mutations is associated with resistance to a wide array of therapeutics that are currently used as first-line treatment in NSCLC, including platinum-based therapies and EGFR tyrosine kinase inhibitors. Since TP53 mutations occur in over 50% of all NSCLC patients, there is a pressing medical need for more effective treatment strategies to improve survival of these patients. In this project, we propose an innovative combination strategy which exploits the presence of mutant p53 by targeting the cellular redox balance. Increased oxidative stress is a hallmark of cancer cells, which makes them more vulnerable to induction of reactive oxygen species (ROS). P53 plays a crucial role in sensing and removing oxidative damage to DNA, and inactivating mutations in the TP53 gene attenuate this function. In addition, it was shown that mutant p53 is able to suppress the function of major antioxidant factors. Therefore, mutant p53 renders cancer cells even more susceptible to the induction of oxidative stress. Besides p53, the poly (ADP-ribose) polymerase 1 (PARP-1) protein plays and important role in the repair of ROS-induced DNA-damage. This led us to explore the potential of combining oxidative stress induction, using the compound APR-246, with the targeted inhibition of the PARP-1 protein, using olaparib. In our lab, this combination strategy showed promising in vitro results in NSCLC cell lines, resulting in strong synergistic interactions in the presence of mutant p53. Following our promising data, this project aims to translate this novel and selective combination strategy to the clinic. In this preclinical study we will explore the combination of two oxidative stress-inducing compounds, APR-246 and auranofin, in combination with the PARP-1 inhibitor olaparib. We will study the predictive value of mutant p53 and the role of ROS in the synergistic cytotoxic effects in NSCLC cell lines. Since oxidative stress and mutant p53 are characteristics that are also frequently observed in other tumor types, we will expand our study to pancreatic ductal adenocarcinoma in vitro.

Researcher(s)

• Promoter: Deben Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This gift is used for cancer research at the Center for Oncological Research to develop novel combination treatments for cancer types with a hig need, as well as for biomarker research and gaining new insight into resistance mechanisms.

Researcher(s)

• Promoter: Lardon Filip

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Everolimus is a targeted therapy commonly used for patients with advanced pancreatic neuroendocrine tumors (PNETs). Unfortunately, after a while patients develop resistance, seen as progression on medical images. Earlier detection of resistance allows a quicker change to more effective therapies, results in better patient outcome, spares patients from ineffective treatment and reduces costs for society. Building on cell line data, fusion genes will first be studied in everolimus-naïve PNET patients as they may represent interesting genetic markers. For further experiments, tissue and monthly blood and urine samples from 30 PNET patients starting everolimus treatment will be collected (EVEREST trial). To identify the first resistance-predicting mutations, the DNA sequence of tumor tissue before and after everolimus-resistance will be compared. Next, we will study the possibility of detecting predictive mutations in non-invasively obtainable tumor DNA fragments in blood and urine (CtDNA) and of using serial CtDNA level measurements as a follow-up marker, both aiming at earlier detection of everolimus-resistance. CtDNA level is estimated by detection of tumor-specific mutations in serial plasma and urine samples. These mutations should be present at baseline and are selected based on the tumor's genetic profile, the experiment on fusion genes, previously obtained results and literature. We expect to detect a rise in CtDNA level when resistance develops.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: Boons Gitta

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

We will study the contribution of hypoxia-inducible factors (HIF) to innate immunosuppression in glioblastoma (GBM) in hypoxia. The capacity of HIF inhibitors combined with the immunostimulant poly(I:C) to eliminate GBM cells will be studied in hypoxic cocultures of human GBM cells, natural killer cells and macrophages. This study will elucidate mechanisms of GBM-mediated immunosuppression and will generate valuable new insights for the development of novel efficacious immunotherapeutic strategies to treat GBM.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Fellow: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In order to provide cancer patients with personalized treatment, molecular understanding of the tumor is indispensable. Therefore, tumor biopsies are needed. However, tissue biopsies might put the patient at risk and are encumbered by heterogeneity and suboptimal tissue acquisition. On the other hand, circulating tumor DNA (ctDNA) and RNA (ctRNA) in liquid biopsies are not only of interest during the initial work-up of a cancer patient, but also because of this approach allows monitoring of the disease during treatment, including the detection of acquired resistance, which can enable a fast switch to an alternative therapy. In this project we will evaluate the use of plasma, platelets and urine as liquid biopsy in the setting of real-time disease monitoring in a patient-friendly way. We will concentrate specifically on two tumor types with poor prognosis, i.e. non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). Investigating urine as non-invasive sampling method and the value of liquid biopsies to monitor response to immunotherapy are two major innovative goals of this project. As the first objective, we will investigate the correlation between blood, urine and tumor tissue of NSCLC patients for the detection of targetable mutations. For the first time, real-time follow-up will be established by screening the ctDNA and ctRNA from blood and urine samples of not only EGFR mutated NSCLC patients, but also ALK- and ROS1 translocated patients during tyrosine kinase inhibitor (TKI) therapy for known and novel resistance mechanisms. Furthermore, the prognostic and predictive value of the quantification of mutated ctDNA and ctRNA in blood and urine will be examined. As the second objective, KRAS mutated NSCLC patients as a non-targetable mutation will be included in order to correlate the mutational status of blood, urine and tumor tissue. The innovative aspect is that both patients undergoing surgery with curative intent and patients undergoing chemotherapy will be included. Furthermore, a proof-of-concept study with blood and urine samples from PDAC patients before and during neoadjuvant therapy and pre- and post-surgery will be performed to assess the necessity and success of the therapy. The third objective is to develop liquid biopsy-based assays inn order to monitor the immune system and tumor load during immune therapy, which is now hampered by the concept of pseudoprogression and the lack of reliable biomarkers. At the moment there are no reliable data on the evolution of tumor necrosis during immune therapy. We will evaluate if monitoring immune makers and proliferation via liquid biopsy can predict which patients benefit of this costly therapy. To conclude, the results of this study will boost implementation of liquid biopsies (plasma and/or urine) in routine clinical care to facilitate personalized treatment of cancer patients.

Researcher(s)

• Promoter: Pauwels Patrick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

There is a presently unmet need for improvement of the outcome in patients with non-small cell lung cancer, who present with locoregional extension, are not fit for concurrent chemoradiotherapy and are sequentially treated with induction chemotherapy followed by definitive radiotherapy. The present project aims at reducing their locoregional relapse rate. We hypothesize that the administration of oral metformin during radiotherapy will decrease the hypoxic fraction of tumour cells which are then better targeted by definitive radiation and become apoptotic. This will be evaluated using a randomised design where all patients will receive definitive radiotherapy with or without metformin. In addition, the validated biomarker of tumour hypoxia 18FMISO PET scintigraphy, and biomarkers of resistance, apoptosis and glucose metabolism will be evaluated for their potential predictive value.

Researcher(s)

• Promoter: van Meerbeeck Jan

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

There still is a large unmet need to improve the diagnosis, treatment and treatment monitoring of patients suffering from Malignant Pleural Mesothelioma (MPM). In other cancer types, the detection of genomic alterations, resulting in the identification of actionable or prognostic biomarkers, has been proven helpful to improve treatment. Hence, the objectives of this research project are: (i) to gain insight into recurrent, actionable genetic alterations in MPM, which can be useful to monitor disease progression and treatment effectiveness; (ii) to understand the genetic factors involved in resistance to chemotherapy and (iii) to explore the detection of genetic alterations in circulating tumour DNA for its potential in early diagnosis and disease monitoring. To achieve this, a meta-analysis will be performed on in-house and publicly available sequencing data, samples of responding and non-responding patients will be sequenced by whole exome sequencing, and serial blood samples of MPM-patients will be analysed.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: Van Camp Guy

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a frequently used treatment modality in advanced pancreatic neuroendocrine tumors (PNETs), since a placebo-controlled phase III trial demonstrated an increased progression-free survival in the everolimus monotheraphy arm. Somatostatin analogues (SSA), such as octreotide and lanreotide, have been used for over 25 years for symptom control in hormone-secreting PNETs. Additionally, recent studies have demonstrated an anti-proliferative effect in PNETs. Initial phase II studies have shown the feasibility and safety of combining both treatments in patients and both drugs are frequently combined in practice. As both treatment modalities only rarely induce objective response (OR) according to the imaging-based RECIST criteria, follow-up of treatment efficacy remains challenging on imaging, as disease stabilization (SD) is often the treatment target. Measuring circulating tumor DNA (CtDNA), shedding directly from the tumor mass and detectable through a non-invasive blood sample, has been correlated to targeted treatment response in colorectal cancers, but has not yet been studied in PNETs and could be a disease progression marker before it is apparent on imaging. Additionally, no predictive biomarkers currently exist to determine which patients benefit most from combined everolimus and octreotide treatment. In this prospective, multi-center, proof-of-concept clinical trial, 30 patients will receive combination treatment with everolimus and octreotide. Primary outcome will be feasibility of treatment follow-up through CtDNA markers. Tumor-specific mutations will be identified through next-generation sequencing of formalin-fixed paraffin-embedded (FFPE) tumor tissue. These tumor-specific mutations will be quantified in CtDNA using digital-droplet PCR during treatment. Feasibility is defined as detection of an increase of 20% of selected CtDNA markers 2 months before progression, according to RECIST, is apparent on imaging. Secondary endpoints include identification of a predictive biomarker for time to progression using ultra-deep next generation sequencing of FFPE tumor tissue, overall response rates, time to progression and safety of the combination treatment according to the Common Terminology Criteria for Adverse Events 4 (CTC-AE 4).

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Currently, there is an explosive interest in novel molecular targeted agents for cancer therapy and new approaches to mitosis inhibition target cardinal regulatory proteins, like polo-like kinase 1 (Plk1). Based on our previous promising findings with the Plk1 inhibitor volasertib, the overall objective is to further decipher the Plk1 pathway as a target for drug development. As such, this project aims to draw conclusions on the therapeutic potential of Plk1 inhibition, which will be investigated in vitro and in vivo, with emphasis on the impact of a hypoxic microenvironment, the role of combination therapy and the molecular pathways involved in NSCLC.

Researcher(s)

• Promoter: Lardon Filip
• Fellow: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The introduction of targeted therapies is now at the forefront of personalised medicine in cancer treatment. After the initial promise of targeted therapies, drug resistance is however emerging as the major obstacle to progress in this field. In this project, we will focus on identification of new combination therapies to overcome intrinsic and acquired resistance to cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Hereby, we will concentrate specifically on head and neck squamous carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Center for Oncological Research (CORE) Antwerp. First, we will screen for new drug combinations by next-generation whole-exome sequencing and tumour kinome profiling of cetuximab-sensitive versus -resistant (intrinsic and acquired) HNSCC cell lines. Next, based on an integrative analysis of both the genetic profile and the kinome profile of cetuximab resistance, new combination treatments can be designed rationally to overcome cetuximab resistance. The molecular pathways underlying the cytotoxic effects of the selected compounds, in combination with chemotherapy and/or irradiation, will be investigated thoroughly, with focus on the hypoxic microenvironment as an important additional cause of therapy resistance. In conclusion, based on our screening results, new combination therapies will be designed rationally in order to thwart resistance to EGFR-targeting agents. Successful combinations will be forwarded into animal studies and ultimately into a clinical trail to demonstrate feasibility of the most promising combination therapy to treat HNSCC patients.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) retains its position as the most lethal type of cancer with around 1.3 million deaths per year worldwide and a marginally improving 5-year overall survival rate which remains below 20%, pointing to the need for new therapeutic options. Immunotherapy, in which the patient's immune system is used to selectively eliminate cancer cells, is considered a very promising candidate. Results of the recently approved immunotherapeutic agent nivolumab underscore the potential of immunotherapy in NSCLC, but also leave room for improvement. This study will focus on the CD70-CD27 signaling pathway as an interesting novel target to enhance anti-tumoral immune responses in NSCLC in combination with low doses of chemotherapy. CD70 is a member of the tumor necrosis factor family and its expression is normally restricted to activated T and B cells. Constitutive expression of CD70 by tumor cells can facilitate immune evasion by increasing the amount of suppressive regulatory T cells, inducing T cell apoptosis and skewing T cells towards T cell exhaustion. Previously, we have detected constitutive overexpression of CD70 in NSCLC tumor specimens, also in patients that lack other targeted treatment options. This CD70 expression can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Our preliminary data show that the combination of anti-CD70 therapy with low doses of chemotherapy significantly increases cytotoxicity of the drug, compared to single treatment regimens. The main objective of the current project proposal is to rationally design and to preclinically evaluate a combination therapy of chemotherapy with CD70-targeted immunotherapy as a novel treatment option for patients with NSCLC.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Rolfo Christian
• Co-promoter: Van Schil Paul

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In this project we will perform a randomized controlled phase II study in which we test a therapeutic cancer vaccine comprising WT1 mRNA-loaded autologous dendritic cells. The primary aim of the study is to investigate the efficacy of the vaccine for AML patients in complete remission at high risk of relapse, both at the level of disease-free survival and overall survival.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and is characterized by a poor prognosis.The cancer cells reside in a hypoxic environment, which supports tumorigenesis, amongst others via suppression of immunity. A burning question is whether plasma as an ionized gas is able to kill cancer cells in a way that makes the immune system active, also known as 'immunogenic cell death'. In this study, we will investigate whether plasma induces immunogenic cell death in glioblastoma cells and whether it can activate immune cells. The effect of hypoxia will also be investigated. We collect these data to gain more insight into the mechanism of action of plasma as a necessary component to obtain approval of a new therapy and to lay the foundation to examine combination therapies in the next phase of the project.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van Loenhout Jinthe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This research project focuses on DFNA5 based upon strong indications for its role as tumour suppressor gene, its function in apoptosis and its potential role as early biomarker in cancer. DFNA5 was identified in 1998 in our lab, as a gene causing autosomal dominant non syndromic hearing loss [3]. Since then, a number of papers on DFNA5 have been published pointing towards a possible involvement in cancer [4-15].

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Camp Guy
• Fellow: Croes Lieselot

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer metastases is responsible for 90% of the cancer related deaths. Due to an increased knowledge of the biology of cancer, more patients are referred to targeted therapy. The efficacy of these drugs depends on the molecular characteristics of the cancer cells. In addition, recent research has shown that molecular characteristics of cancer cells can change during cancer progression and metastasis. Since it is practically difficult to sample metastatic tissue repeatedly, investigating alternative matrices is imperative, paving the way for liquid biopsies. One possibility is to evaluate the molecular characteristics of circulating tumor cells, obtained from peripheral blood. However, before these cells can be used as matrix for molecular diagnostics, is should be evaluated if these CTCs have the same characteristics as the primary or metastatic tumor cells. In addition, due to heterogeneity in the primary tumor/metastases, is should be evaluated how many CTCs need to be analyzed in order to capture the dominant driving clones. In order to evaluate this, genomic changes from CTCs will be compared to the genomic composition of the primary tumor and the metastases. If successful, this project will allow a translation of liquid biopsies from the bench to the bedside, sparing patients from difficult and painful treatments.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Peeters Marc
• Fellow: Brouwer Aaltje

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Support for the development of novel combination strategies with immunotherapy to treat solid tumors, as well as to investigate immune escape mechanisms of cancer cells and to characterize the tumor immune microenvironment

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This research community is focused on gaining a better insight in the relationship between the physicochemical properties of nanomaterials for drug delivery and in vivo imaging on the one hand and their biological behavior with a focus on biodistribution in biological fluids, recording and processing in cells and toxicity on the other hand.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Mertens Inge
• Promoter: Sobott Frank

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer related death in the western world and incidence is still rising. Due to its rapidly progressive nature and lack of early symptoms, up to 80% of the patients present itself late with advanced or metastatic disease. This results in an extremely poor prognosis and a 5-year survival below 5%. Current treatment options for PDAC are limited since only 10-15% of the patients are eligible for curative surgical resection. The remaining patient population is treated with chemotherapy which has only modest improvements in survival due to chemoresistance in the majority of patients. The tumour microenvironment (TME) is believed to be a major confounding factor involved in failure of different therapeutic strategies. A hallmark of this TME in PDAC is the strong desmoplastic reaction which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC). By acting as a mechanical and functional shield around the tumour, it plays a central role in the development, progression and invasion of PDAC and also creates an immunosuppressive TME. In this strategic basic research project, novel combination immunotherapies will be investigated in search for better treatment options for PDAC patients. Both immune stimulation and inhibition of immune suppression will be employed, with a special focus on the TME.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc
• Fellow: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Mertens Inge

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Bladder cancer is a common urologic cancer with +/-2340 new cases in 2012 in Belgium. The current golden standard for bladder cancer diagnosis is a combination of invasive and non-sensitive urine cytology and cystoscopy. The overall cost of bladder cancer treatment is high due to the long term monitoring of non-muscle –invasive bladder cancer and the treatment of recurrences. Non-invasive, inexpensive and highly sensitive bladder cancer biomarkers are urgently demanded to improve diagnosis and monitoring, and to decrease patient morbidity. Urine exosomes are small membrane vesicles that are released by the epithelia of the complete urogenital tract and contain a variety of molecules such as signal proteins and/or peptides, microRNAs, mRNAs and lipids. In this project we aim to provide urologists with a highly selective, specific and non-invasive exosomal protein signature to diagnose and monitor bladder cancer patients. Therefore we will implement 4 work packages to isolate, identify and compare the exosomal proteome from urine samples of healthy volunteers versus low and high grade bladder cancer patients.

Researcher(s)

• Promoter: Mertens Inge

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project