Hans Prenen professor

Research Hans Prenen

Research team

FOLICOLOR trial: Following therapy response through liquid biopsy in metastatic colorectal cancer patients. 01/02/2024 - 31/01/2029

Abstract

In Belgium, yearly approximately 1600 patients are diagnosed with mCRC, and have a 5-year overal survival (OS) rate below 20%. Therapy generally consists of chemotherapy and targeted therapy, and the response to therapy is evaluated every 8 weeks using imaging techniques (i.e., CT scans) and tumor markers. However, this follow-up method is not optimal and delays detection of progressive disease (PD). This poses challenges in care for these patients given their poorer prognosis as compared to other common cancer types. Late detection of PD delays the switch from the current therapy to a new therapy. In this case, the optimal therapeutic window for the new therapy is missed and there is longer exposure to unwanted toxicities of the current therapy. These factors contribute to a worse Quality of Life (QoL) both directly and indirectly, and thus impact patient outcomes. Novel biomarkers like circulating tumor DNA (ctDNA) have shown promise in mitigating these shortcomings of the current follow-up techniques. These biomarkers are obtained through LBs, which harbor ctDNA that originates directly from the tumor. The analysis of ctDNA has shown its utility in various settings in oncology, and specifically for mCRC, pilot studies, including our research, indicate that follow-up of patients with NPY methylation-based ctDNA analysis can detect PD earlier than conventional techniques. One such pilot study is the FOLICOLOR lead-in study, which showed that LBs can detected PD earlier than the current techniques (manuscript in preparation). The NPY methylation-based ctDNA analysis was validated during this study, and optimal cut-off for PD detection was determined. Within the randomized FOLICOLOR trial, this promising NPY methylation-based ctDNA analysis is applied to compare treatment follow-up via LBs to follow-up through the current techniques. We hypothesize that earlier PD detection will lead to earlier identification of patients who do not respond to the current line of therapy, which will prompt earlier switch to a new line of therapy. This will prevent unnecessary toxicities from the current therapy and allows the start of a new line of therapy in a more suitable therapeutic window leading to enhanced treatment efficacy, potentially improving OS and QoL. Frequent follow-up will also empower patients and will stimulate true joint decision-making on therapy decisions. In the prospective, randomized, open-label, multicentric, phase II FOLICOLOR trial, 150 mCRC patients starting 1st line therapy are randomized to one of the two study arms: the control arm (with follow-up through CT scans and CEA every 8 weeks as part of the standard of care (SOC)) or the study arm (with follow-up through LBs every 4 weeks, while still receiving CT scans and CEA every 8 weeks as part of the SOC). As the aim of this project is to reduce the overall toxicity in these patients, in order to improve QoL, the primary endpoint is to assess the difference in time to deterioration (TTD) in both arms. Secondary endpoints include difference between both arms in terms of progression-free survival (PFS), 3-year OS, toxicity, and long-term QoL. Finally, exploratory endpoints like comparison of ctDNA and CEA in PD prediction, association of ctDNA and PFS, and the development of a decision aid are included.

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  • Research Project

Liquid biopsies in digestive and neurendocrine neuroplasms. 01/02/2023 - 31/01/2026

Abstract

Digestive neoplasms include include a wide range of tumortypes in the upper and lower digestive tract. In Belgium, 12740 new cases of digestive neoplasms were reported (16% of total new reported cancer diagnoses) (source: Belgian Cancer Registry). A large proportion of these tumors is diagnosed at an advanced stage, resulting in high morbidity and mortality rates as the ideal therapeutic window is missed. Despite their high incidence and prevalance, there is a lack of (1) tools for early diagnosis, and lack of (2) good quality follow-up tools tot detect progressive disease (PD) earlier. There is urgent requirement of developement of accurate non-invasive biomarkers to answer to these unmet needs. Neuroendocrine neoplasms (NENs) form a group of relatively rare malignancies, and originate frequently from organs of the digestive tract. In Belgium, more than 1000 new NEN cases were reported in 2018 and the 5-year prevalence of all NEN cases was estimated at 3400 patients (Belgian Cancer Registry). Because of their relatively indolent nature, long-term follow-up is necessary to assess tumor growth and response to treatment. Currently, follow-up is performed using techniques based on imaging and evaluation of protein biomarkers, neither of which is ideal. The development of accurate noninvasive biomarkers in NEN patients represents one of the most important unmet needs according to the European Neuroendocrine Tumor Society (ENETS). Recently, we demonstrated that sequential genome-wide copy number alteration (CNA) profiling of circulating cell-free DNA (ccfDNA) could serve as a new, non-invasive biomarker for follow-up of patients with metastatic NEN. Additionally literature shows that similar principle of analysis of ccfDNA in digestive neoplasms, has great potential too as a non-invasive biomarker for early diagnosis of these tumors, and better follow-up of patients with metastatic disease. Moreover, it was revealed that even ccfDNA without apparent CNAs contains informative genomic signatures, that allow for better differentiation between healthy individuals and cancer patients. Additionally, preliminary studies already revealed great potential for methylation profiling of ccfDNA as a biomarker in NENs and digestive neoplasms. However, investigating the potential clinical impact of ccfDNA in extensive cohorts of NEN patients and patients with digestive neoplams, given clinical implementation remains difficult due to restricted numbers of patients and/or incomplete datasets. The project aims to investigate the potential impact of ccfDNA on clinical decision-making and facilitate the implementation of ccfDNA assays in a clinical setting, with the ultimate goal of improving care and outcome of patients with NENs and digestive neoplasms. To achieve this, we pursue these objectives: 1. Setting up a systematic collection of liquid biopsies and clinical data from a large population of patients with NENs and digestive neoplasms to achieve an adequate sample size for ccfDNA analysis. 2. Validating two novel ccfDNA analyzing techniques for assessment of the presence and quantification of circulating tumor DNA (ctDNA) in liquid biopsies derived from an extensive cohort of patients with NENs and digestive neoplasms. 3. Monitoring tumor fraction (i.e. ctDNA quantities) over time in sequential plasma samples from NEN patients using two ccfDNA assays and correlating this with time to progression (according to RECIST 1.1 criteria) to explore the predictive efficacy of ccfDNA analysis and thereby evaluate its biomarker potential for patient follow-up.

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  • Research Project

Development of an image-based multiparametric drug response signature to predict clinical therapy response in cancer patients from ex vivo tumoroid screenings. 01/10/2022 - 30/09/2026

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.

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  • Research Project

Reinvigorating the antitumor immunity in human breastand cervical cancer with an innovative RANK(L) targeted combination strategy. 01/11/2021 - 31/10/2025

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.

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  • Research Project

Combining targeted therapy and immunotherapy to improve survival and quality of life of head and neck cancer patients. 01/03/2021 - 28/02/2025

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)

Research team(s)

Project type(s)

  • Research Project