Research Christophe Deben

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

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

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

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

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

The corneal endothelium is the innermost layer of the human cornea, the eye's transparent window. A dysfunctional endothelium leads to corneal opacification, which is a common cause of corneal blindness worldwide and results in an unavoidable need for a transplantation. Unfortunately, the global donor shortage causes very long waiting lists. A pharmacological compound to stimulate in vivo corneal endothelial regeneration therefore is a very interesting alternative treatment to reduce the reliance on donor corneas. However, there are many limitations regarding the traditional drug discovery pipelines such as high cost and long development times. Moreover, the corneal anatomy hampers drug permeation. The aim of my PhD therefore is to tackle both these limitations so to deliver an innovative pharmacological treatment. Hence, this project proposes a high throughput biological screening of repurposed drugs, i.e. the screening of formerly approved compounds. This biological data will serve to develop and train a virtual compound screening model to predict additional potential lead compounds. The high throughput screenings together with a thorough characterization and optimalization of the physico-chemical properties of the main hits, will lead to the identification of one repurposed lead compound. Eventually, I will assemble this compound together with a corneal permeability enhancer into an inventive eye drop that facilitates corneal penetration to reach the endothelium.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Deben Christophe
• Co-promoter: Van den Bogerd Bert
• Fellow: Witters Charissa

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The corneal endothelium lies on the interior of the cornea, which is the window of our body. Proper function of this corneal endothelium is essential to obtain a crystal-clear cornea. Current consensus holds that endothelial cells do not display any significant regenerative capacity. Damaged or non-functional cells may consequently lead to corneal blindness. In this regard, stimulation of the regenerative capacity of the corneal endothelium is of exceptional importance in the search for new therapeutic possibilities. Furthermore, for in vitro biomedical research the culture of primary corneal endothelium is an extremely time-intensive process without full guarantee of cell expansion. In this project we intend to provide a solution for these issues by pharmacological stimulation of the regenerative capacity of corneal endothelial cells through re-orientation of available drugs. During this project various molecules will be subject to a tri-fold screening method (cellular, subcellular and molecular), which leads to the selection of a regenerative compound for corneal endothelial purposes. On the one hand, specific ROCK-inhibitors will be tested, given their growth potential within tissue regeneration. On the other hand, commercially available drug libraries will be screened for compounds with known activity for regenerative capacities.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Deben Christophe
• Co-promoter: Van den Bogerd Bert

Research team(s)

• Translational Neurosciences (TNW)

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

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

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

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

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

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

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

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

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

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 via the receptor NKG2D. For this, we will study (I) the p53 dependent induction of NKG2D ligand expression and NK cell targeting chemo- and cytokine secretion in a panel of NSCLC cell lines; (II) NK cell-mediated NSCLC tumor cell killing in co-culture experiments; and (III) the potential additional antitumor effect of interleukin 15 as potent NK cell activator. 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)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Pauwels Patrick
• Fellow: Deben Christophe

Research team(s)

Project type(s)

• Research Project