Research Marc Peeters

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

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

Inspired by the mission of the EU commission, this project commits to tackle a major societal challenge, i.e. fighting cancer. A striking target for 2030 has been set by the EU: more than 3 million lives saved, living longer and better, achieve a thorough understanding of cancer, prevent what is preventable, optimize diagnosis and treatment, support the quality of life of all people exposed to cancer, and ensure equitable access to the above across Europe. This project contributes to (early) diagnosis and follow up of the disease. More and more biomarkers are discovered and validated for cancer and the highly precise determination thereof is high on the priority list, necessitating analytical devices that allow rapid and accurate analysis with high sensitivity. Electrochemical biochips are an emerging tool for point-of-care diagnostic systems due to their inherent high sensitivity and cost and time effectiveness. We propose the combined use of electrochemical detection with a light-triggered sensing technology for the specific and selective photoelectrochemical detection of low concentrations of cancer biomarkers (i.e. KRAS mutations), also allowing us to detect a panel of cancer biomarkers. Detection and quantification of the selected target sequences will be performed in tissue and liquid biopsies, to ensure the translation from a lab technology to a device for clinicians and even patients.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Koljenovic Senada
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

• Antwerp Electrochemical and Analytical Sciences Lab (A-Sense Lab)

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 have a direct impact on patients' lives. Over the past few years, liquid biopsies have gained interest as a minimally-invasive 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 cell-free 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 unable 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: Van Camp Guy
• Co-promoter: De Wael Karolien
• Co-promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Fellow: Mariën Laura

Research team(s)

• Medical Genetics (MEDGEN)

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

In Flanders (Belgian region), a colorectal cancer (CRC) screening programme has been in place since 2013 to reduce CRC incidence and related mortality1. Next to these benefits, cancer screening may cause harm for the participants such as interval cancers (CRC 16%2), a false sense of safety or anxiety due to false positives and adverse events of follow-up colonoscopy (e.g. bleeding, colon perforation). There is increasing international recognition that target groups for cancer screening have to be fully aware of the benefits and potential harms of screening in order to make an informed choice. In Flanders and a large part of the EU, this is currently not considered in full, as information shifts towards nudging the benefits of cancer screening. To what extent a person makes an informed decision about cancer screening with the given information is unknown in Flanders, as there are no measurement tools available. Additionally, there are no widespread tools that can support making an informed decision about CRC screening, such as a shared decision making (SDM) tool for general practitioners (GPs) and their vulnerable patients (both end-users in this project). GPs in Flanders have been asking for such a visual SDM tool regarding CRC screening for almost 2 years now (Personal communication, Domus medica*, 2021). At the same time, particularly the vulnerable population requires more accurate, clear and well balanced information which for them is currently not available, which could result in distrust and barriers to understanding the information (Personal communication, 10 stakeholder organisations, 2021). Therefore, the largest impact can be created for these end-users and the current health equity gap for cancer screening can be tackled. To tackle these long-lasting problems, the primary goal of this project is to develop and test an SDM tool through co-creation with the end-users tailored to their needs. Included in this tool, a personalised machine learning (AI) model will enable GPs and patients to discuss CRC on a more personal level regarding the patient's risk of CRC (risk-stratified SDM-tool). All this will be realised in the current daily practice of Flemish GPs with the support of Domus Medica. The primary outcome of the project is to assess the impact of the risk stratified SDM tool on patients' informed choice regarding CRC screening. Secondary outcomes are: 1) To assess the impact of the SDM tool on patients' attitude towards screening, intention to participate, decision conflict, confidence in decision making, anxiety about CRC and screening participation, perceptions about benefits and risk of screening and, 2) To assess GPs' experience with the SDM tool in terms of usability, time requirement, satisfaction with the tool and their perceptions about the effect of the tool on their patients. Current difficulties of reaching the vulnerable population by postal mail will be addressed via GPs. This project is considered high impact due to its scalability on the one hand and its clinical relevance towards the vulnerable population on the other. In the current CRC screening environment, this project will have an impact on the vulnerable population and through transferability of the SDM tool to the general population a possible ~ 900.000 annually invited persons could be reached. Transferability will be possible as the SDM tool will be created through Universal Design (accessible to everyone). *Domus Medica represents the interests of the general practitioners in Brussels and Flanders.

Researcher(s)

• Promoter: Van Hal Guido
• Co-promoter: Peeters Marc

Research team(s)

• Social Epidemiology & Health Policy (SEHPO)

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

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

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

Colorectal cancer (CRC) and breast cancer are amongst the most common and deadliest cancers worldwide. Early detection through current screening programs for both cancers have reduced mortality, but important limitations of these methods, such as limited sensitivity, limited specificity and invasiveness, remain. There is a need for a new, minimally-invasive, cost-effective and very sensitive diagnostic test for screening and early cancer detection. Methylated circulating tumor DNA (metctDNA) biomarkers have shown great potential to discriminate between normal tissue and tumors. MetctDNA can be detected in a minimally-invasive manner using liquid biopsies, such as plasma. Currently, DNA methylation is studied using bisulfite conversion followed by next-generation sequencing or droplet digital PCR. However, disadvantages including DNA degradation, non-optimal sensitivity and specificity of subsequent techniques and limited multiplex capacities still need to be overcome. At this moment, there exists no efficient technique for the simultaneous analysis of several methylated regions in ctDNA in one assay. In our research group, we aim to develop a new, sensitive multi-region metctDNA based bisulfite-free detection technique. The technique will be used in this project to detect differential methylation signatures between normal tissue, pre-cancerous lesions and tumors. With this approach, we aim to develop a new and better assay for screening and detection of CRC and breast cancer.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Co-promoter: Van Hal Guido
• Fellow: Neefs Isabelle

Research team(s)

• Medical Genetics (MEDGEN)

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 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

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

Based on the strong need for more targeted, tolerable and durable treatment strategies that could postpone or even prevent recurrence of disease in the most common adult malignant brain tumor, we embarked on a phase I/II clinical trial assessing frontline treatment with autologous dendritic cell (DC) vaccines loaded with glioblastoma-associated tumor antigen Wilms' tumor 1 in conjunction with conventional chemoradiation following surgery in adults with glioblastoma multiforme (GBM; NCT02649582). Childhood high-grade glioma (HGG, including GBM) and diffuse intrinsic pontine glioma (DIPG) are rare aggressive brain tumors. In the absence of a standard of care, treatment is mostly adapted from adult schedules, resulting in 5-year survival rates of less than 5% and 1% after diagnosis, respectively. With limited advanced investigational treatment options for this vulnerable patient population, we strive to extend our clinical study to the pediatric application. Ultimately working towards the clinical valorization of an adjuvant DC-based immunotherapy approach, health care evaluation is warranted. To this extent, we will include collection of patient-reported outcome on how the study therapy is experienced throughout time in the response evaluation of all study patients. As the search for biomarkers is gaining momentum in the rapidly evolving cancer immunotherapy landscape, we are also continuously expanding the screening assays on clinical patient material. The present project proposal is designed to allow completion of the intended adult GBM patient recruitment number and to extend the trial, innovating on the pediatric application of DC vaccination, health care evaluation and emerging therapeutic biomarker research. Within the context of hard-to-treat brain tumors, this study and its specific design will add a new dimension to our translational and clinical DC vaccine programs by investigating whether DC vaccination can be combined with first-line chemoradiation treatment of adult GBM and childhood HGG and DIPG patients and whether this combination leads to tumor-specific immune responses and improved survival. Exploration of patient-reported outcomes will help to improve symptom management, functional status and overall quality of life and will provide necessary information for future clinical valorization of this type of personalized medicine. In depth research on clinically valuable biomarkers will allow us to make a significant contribution to the broader (immunotherapy-oriented) scientific community.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: De Praeter Mania
• Co-promoter: Lion Eva
• Co-promoter: Norga Koenraad
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

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

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

Improvement of first-line treatment for cancer patients with a high tumor recurrence rate and low effective treatment options, such as pancreatic cancer (PC), is warranted. Pancreatic cancer is a devastating disease with a 5-year survival rate below 5%, depending on the specific stage of disease when it is diagnosed, rendering it the 4th most common cause of cancer-related death worldwide. Even those who are eligible for curative-intent resection and conventional adjuvant treatment will nearly all die of their disease due to the high tendency towards recurrence. Adjuvant treatment with gemcitabine after resection of PC decreases recurrence rate, but the disease-free survival of these patients stays dismal with a 5-year survival rate below 21%, underscoring the need for new adjuvant regimens. The combination of gemcitabine with immunotherapy might improve outcome as suggested by some studies, but available data is so far limited to a few early-phase uncontrolled clinical trials. Interleukin (IL)-15-transpresenting dendritic cells (DCs) are a promising armament for immunotherapy of PC. Complementary to current treatments, DCs as quintessential antigen-presenting cells of the immune system can activate the antitumor immune system to attack pancreatic cancer cells. Preclinical data demonstrate the therapeutic potential of these innovative IL-15-transpresenting DCs evidenced by superior activation of the antitumor immune system to attack cancer cells. Since this will be the first-in-human use of IL-15-transpresenting DCs, the objectives are to test the safety, feasibility and immunopotency in patients with refractory solid tumors, the prototypic cancer patient population for phase I trials. This phase I clinical study is pivotal for future testing of this promising IL-15-transpresenting DC vaccine as adjuvant therapy to current anticancer regimens aiming to improve the standard of care of cancer patients with a high unmet medical need.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Lion Eva
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

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

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

Inspired by the mission of the EU commission, this project commits to tackle a major societal challenge, i.e. fighting cancer. A striking target for 2030 has been set by the EU: more than 3 million lives saved, living longer and better, achieve a thorough understanding of cancer, prevent what is preventable, optimise diagnosis and treatment, support the quality of life of all people exposed to cancer, and ensure equitable access to the above across Europe. This project contributes to (early) diagnosis and follow up of the disease. More and more biomarkers are discovered and validated for cancer and the highly precise determination thereof is high on the priority list, necessitating analytical devices that allow rapid and accurate analysis with high sensitivity. Electrochemical biochips are an emerging tool for point-of-care diagnostic systems due to their inherent high sensitivity and cost and time effectiveness. We propose the combined use of electrochemical detection with a light-triggered sensing technology for the specific and selective photoelectrochemical detection of low concentrations of cancer biomarkers (i.e. KRAS mutations). In this project we will focus on the development of a multiplexed 96-well plate-based detection of a panel of cancer biomarkers. Detection and quantification of the selected target sequences will be performed in liquid biopsies, to ensure the translation from a lab technology to a device for clinicians and even patients.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Koljenovic Senada
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

• Antwerp Electrochemical and Analytical Sciences Lab (A-Sense Lab)

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

Inspired by the mission of the EU commission, this project commits to tackle a major societal challenge, i.e. fighting cancer. A striking target for 2030 has been set by the EU: more than 3 million lives saved, living longer and better, achieve a thorough understanding of cancer, prevent what is preventable, optimize diagnosis and treatment, support the quality of life of all people exposed to cancer, and ensure equitable access to the above across Europe. This project contributes to (early) diagnosis and follow up of the disease. More and more biomarkers are discovered and validated for cancer and the highly precise determination thereof is high on the priority list, necessitating analytical devices that allow rapid and accurate analysis with high sensitivity. Electrochemical biochips are an emerging tool for point-of-care diagnostic systems due to their inherent high sensitivity and cost and time effectiveness. We propose the combined use of electrochemical detection with a light-triggered sensing technology for the specific and selective photoelectrochemical detection of low concentrations of cancer biomarkers (i.e. KRAS mutations), also allowing us to detect a panel of cancer biomarkers. Detection and quantification of the selected target sequences will be performed in liquid biopsies, to ensure the translation from a lab technology to a device for clinicians and even patients.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy

Research team(s)

• Antwerp Electrochemical and Analytical Sciences Lab (A-Sense Lab)

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

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

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

Each year, an estimated 8.2 million people die of cancer. With appropriate detection methods and treatment, many of these deaths would be avoidable. Due to the high incidence and mortality rates, early and accurate diagnosis is paramount for a quick and adequate treatment of patients. Until recently, no truly non-invasive diagnostic methods for the detection of cancer existed. An attractive novel method is the detection of abnormally expressed biological markers manifested during carcinogenesis in so called "liquid biopsies". Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or peripheral blood, are sampled and analysed for disease diagnosis. The analysis of Circulating tumor DNA (CtDNA) in cancer patients is not new and has been performed in the past. However, until now, a strong focus existed on the detection of tumor specific mutations, which has several limitations. The use of methylation markers instead of mutation markers has many advantages and is understudied. We have recently published GSDME as a highly sensitive and specific methylation biomarker for both breast and colorectal cancer. We wish to build upon these data and extend our search for suitable cancer detection biomarkers genome wide. One of the problems with liquid biopsy nucleic acid biomarkers is the limited sensitivity for early detection. Indeed, in early stages of carcinogenesis, many tumor types have low concentrations of CtDNA. Sensitivity can be increased by measuring a multitude of markers simultaneously. However, to date, no efficient techniques exist that allow multi-region methylation analysis in plasma. Therefore, in this project, we will design a novel technique, next generation high resolution methylation detection in plasma of cancer patients and develop a novel multi-region pan-cancer detection assay, based on genome wide methylation tumor data. We believe that this novel technology is able to increase sensitivity 100 - 1000 fold while reducing the cost more than a 100 fold compared to the standard technologies that are used nowadays. Finally, we will validate our novel technique and assay in clinical samples.

Researcher(s)

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

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Each year, an estimated 8.2 million people die of cancer. With appropriate detection methods and treatment, many of these deaths would be avoidable. However, current methods for detection and analysis of treatment response still suffer from major disadvantages. An attractive novel method is the detection of abnormally expressed biological markers manifested during carcinogenesis in so called "liquid biopsies". Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or peripheral blood, are sampled and analysed for disease diagnosis. The analysis of CtDNA (DNA originating from the tumor and present in the blood) in cancer patients is not new and has been performed in the past. However, until now, a strong focus existed on the detection of tumor specific mutations, which has several limitations, such as limited sensitivity. The use of methylation markers instead of mutation markers has many advantages, such as a potentially much higher sensitivity, and is understudied. We have recently published GSDME as a highly sensitive and specific methylation biomarker for both breast and colorectal cancer. In addition, we have analyzed 12 additional frequent cancer types, and we have strong preliminary data that GSDME is about equally sensitive in each of these 14 tumor types analyzed. These data show that GSDME has strong potential as the first true pan-cancer biomarker. In part A of the project, we will focus on GSDME, and test it as a true biomarker in a clinical setting. Next to detection markers, there is also a need for better follow-up markers. Follow-up of cancer patients is currently performed based on clinical, radiologic and tumor marker evaluation, which has limitations. Better follow-up markers have the potential to detect resistance or disease progression earlier. We aim to expand further on these concepts and conduct a clinical trial where we will evaluate the use of GSDME methylation analysis in liquid biopsies as a tool to guide treatment in metastatic colorectal patients and to explore whether GSDME has potential as a follow up biomarker (WP2). Moreover, GSDME has an interesting physiological function. Recent papers have identified Gasdermins, including GSDME, as a completely new type of regulated cell death executioners (RCD). Recently, it was proven that the N-terminal part of GSDME induces RCD through pore-formation and this is a key antitumor mechanism that is inactivated in several tumor types. In a third work package of part A, we will further investigate these fundamental aspects of the GSDME gene and study its involvement in carcinogenesis. One of the problems with liquid biopsy nucleic acid biomarkers is the limited sensitivity for early detection. Indeed, in early stages of carcinogenesis, many tumor types have low concentrations of CtDNA. Sensitivity can be increased by measuring a multitude of markers simultaneously. However, to date, no efficient techniques exist that allow multi-region methylation analysis in plasma. Therefore, in part B of this project, we will design a novel technique that is able to do this. In a previous unpublished analysis, we have shown that the cancer methylome contains a multitude of differentially methylated makers, that hold the potential to be used as pan-cancer biomarkers, and we have developed a bioinformatics analysis pipeline to detect and rank these according to their discriminating power. Using these data, we will develop a novel multi-region pan-cancer detection assay using our novel technique. We believe that our technology is able to increase sensitivity 100 - 1000 fold while reducing the cost more than a 100 fold compared to the standard technologies that are currently used for CtDNA biomarkers. Finally, we will validate our novel pan-cancer detection assay in the clinical samples that were collected in part A.

Researcher(s)

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

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

With an estimated 8.8 million deaths yearly, the cancer burden weighs heavily on populations globally. Early detection of cancer is one of the key aspects that results in improved patient prognosis. In this respect, the analysis of circulating tumor DNA in plasma is potentially a major enhancement over currently used imaging, immunochemincal or histopathological methods. Highly sensitive and specific biomarkers for the most common types of cancer are currently still lacking however. In light of recent publications, DNA methylation holds great promise as a tumour marker, but it is yet to be fully explored in the context of liquid biopsies. Our preliminary data shows that CpG methylation can be used to effectively detect cancer and determine different tumors. Our research group is developing a new, robust, and cost-effective diagnostic assay using methylation markers, termed MeD-smMIPs-seq. This assay will combine methylated DNA sequencing with single molecule molecular inversion probes to target highly informative CpGs and achieve high diagnostic sensitivity while reducing assay costs. The aim of this project is first to identify the most informative differentially methylated regions genome-wide, that can be used as cancer biomarkers in this assay. Secondly, we aim to develop the bioinformatics framework required for new experimental design and downstream data analysis. Finally, we will validate the assay and the computational pipeline in the context of liquid biopsies.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Peeters Marc
• Fellow: Ibrahim Joe

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Early and accurate detection of cancer has great potential to reduce mortality, as treatment is often more successful in early stages. The currently used methods for cancer detection and screening have important limitations such as low sensitivity in early stages and invasiveness. There is a clear need for new minimally invasive, costeffective and sensitive diagnostic tests that are also capable of early cancer detection for all cancer types. Circulating tumor DNA (ctDNA) methylation biomarkers have the potential to be used in such minimally invasive tests for cancer diagnosis. Further studies are however required to improve the insufficient sensitivity and specificity of methylation ctDNA (MetctDNA) based tests. Digital droplet PCR is the golden standard for ctDNA analysis. However, the need for DNA damaging bisulfite conversion and limited targets that can be multiplexed are important disadvantages. Currently no cost effective, efficient and sensitive techniques exists for the analysis of multiple methylation sites in ctDNA. To remediate this, we have obtained in our lab a proof of concept for a sensitive, multi-region MetctDNA based bisulfite-free detection technique. The general aim of this project is to develop this technique into a pan-cancer detection assay. A high sensitivity and pan-cancer performance is expected to be reached by combining 1000 methylation biomarkers with this technique.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Op de Beeck Ken
• Co-promoter: Peeters Marc
• Fellow: Van Houte Alena

Research team(s)

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

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 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

Three UAntwerp research groups (Medicinal Chemistry, Physiopharmacology, MIPRO) recently joined forces for the discovery and study of autophagy modulators as potential oncology therapeutics. Hitherto, this approach has resulted in a joint patent application and several manuscripts that have either been published or are under preparation. Most attention to date has gone to investigation of UAMC-2526, an Atg4B-targeting autophagy inhibitor that was discovered by the project team. This compound has potent in vivo autophagy blocking properties and significant anti-tumoral potential in an in vivo xenograft mouse model of colorectal cancer. To ensure economical valorization interest for UAMC-2526 and the UAntwerp-patented family of compounds to which it belongs, more basic research is required. The balanced package of medicinal chemistry, in vitro pharmacology and in vivo oncology that is presented here, should provide detailed insight in the potential of UAMC-2526 and its analogues as a potential therapeutic agent. In addition, biopharmaceutically optimized follow-up candidates for UAMC-2526 will be delivered. At the same time, this effort will increase the compounds' attractiveness to external economic valorization partners. Finally, this project will also create critical mass for a preclinical research platform on autophagy research at UAntwerp. This platform will unite chemical and biological capabilities in autophagy research that will be highly instrumental to support research programs, but will also be offered to private partners that require expertise in the domain.

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: Martinet Wim
• Co-promoter: Peeters Marc
• Co-promoter: Stroobants Sigrid

Research team(s)

• Medicinal Chemistry (UAMC)

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

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide with a high morbidity and mortality. Although CRC can be cured in most cases when it is detected in its early stages, the treatment of patients with metastatic CRC (mCRC) still has its limitations. Accurate monitoring of tumor disease and appropriate tumor tissue for mutation-analysis before anti-EGFR therapy are lacking. Possible solutions can be found in liquid biopsies. During my PhD, a lot of time and effort has been put in starting up a clinical trial recruiting mCRC patients treated in first-line with targeted therapies. Blood samples are collected at four different time points during treatment for the isolation of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). Our first pilot study on 24 patients has just been finished and reveals exciting results. We find out that it is possible to monitor tumor disease during treatment using mutation and methylation digital droplet PCR (ddPCR) assays on ctDNA and these results were also corresponding with the imaging results. We would like to confirm these results on an expanded study cohort where additional monthly blood samples are collected between time point 3 (first radiographic evaluation) and 4 (disease progression or curative surgery). In this way, we want to investigate whether it is possible to early detect progression, meaning before detection by radiographic evaluation. At this moment, we have the knowledge, the patients (n=40) and the motivation to perform these highly interesting experiments, we only need some extra time. In addition, some additional experiments should be performed on ctDNA of serum samples to make a clear comparison between plasma and serum samples. If our results would indicate that ctDNA isolated from serum samples follows the same trend as plasma samples during tumor disease monitoring, this will be the start of multiple liquid biopsy studies as a lot of serum samples are stored in the biobank of different hospitals. Lastly, we want to finish our study on CTCs. Up to now, we performed already expensive and time-consuming detection and isolation of CTCs. Unfortunately, we did not have the time yet to perform whole genome amplification and mutation detection. It would be very interesting to evaluate whether CTCs reveal the same or additional information compared to circulating DNA. In conclusion, liquid biopsies are promising tools in mCRC treatment. We managed to collect a very interesting patient cohort and showed already some exciting results. Unfortunately, due to lack of time, the majority of the samples has not yet been studied. Thanks to the acquired expertise so far, I believe that we can perform very interesting experiments with a minimal time investment (12 months) which enables me to successfully and proudly finish this PhD.

Researcher(s)

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

Research team(s)

Project type(s)

• Research Project

Abstract

Cytotoxic chemotherapy is a commonly used treatment for curing breast cancer, prostate cancer and lung cancer. Cytotoxic chemotherapy may however also induce serious side effects such as nail changes (e.g., color, brittleness, damages, ...). In its most severe form, this may lead to onycholysis or the releasing of a portion of the nail, which is often preceded or accompanied by severe pain. Nail toxicity is observed at 44% of patients treated with taxanes. Nail toxicity can be avoided or mitigated through the use of ice gloves. Ice gloves are cooled to -20 ° C and worn during a chemotherapeutic treatment. Unfortunately, the use of ice gloves is very painful and therapeutic compliances are limited. This project allows to develop a medical instrument to avoid nail toxicity at cancer patients. The instrument aims to allow a painless and effective prevention of nail toxicity.

Researcher(s)

• Promoter: De Bruyne Guido
• Co-promoter: Goethijn Frank
• Co-promoter: Peeters Marc
• Co-promoter: Verwulgen Stijn

Research team(s)

• Product development

Project type(s)

• Research Project

Abstract

The microenvironment of most solid tumors tends to be significantly more acidic than healthy tissue. Inadequate perfusion, oxygen limitation and cell metabolic changes, are key causative factors for this situation. The acidic pH induces a number of specific genetic, transcriptional and metabolic effects in tumor cells. These are required for survival under increased H+- stress. Evidence is now mounting that these effects also play a major role in tumor progression, invasiveness and the development of multi-resistance to therapy. Two pivotal adaptations related to maintaining intracellular pH homeostasis in an acidic environment, have recently received significant attention: (1) the presence of chronic autophagy in tumors and (2) the overexpression of carbonic anhydrases (CAs), mainly CA IX and CA XII. This project will biopharmaceutically optimize a novel class of specific autophagy inhibitors that target Atg4B. The specific goal of this part of the project is to obtain orally bioavailable and metabolically stable compounds that are fit for in vivo applications. The relevance of these compounds is clear, given the unmet demand for reliable, specific inhibitors in the domain of autophagy. At the same time, the project will evaluate the potential for therapy development of the compounds in the framework of cancer. Finally, the proposal will explore whether a further increase of anti-tumor efficiency can be obtained by combining Atg4B- and CA-inhibitor pharmacophores in a single compound.

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: Martinet Wim
• Co-promoter: Peeters Marc
• Fellow: Tanc Muhammet

Research team(s)

• Medicinal Chemistry (UAMC)

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

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

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

The functional levels of a biological system include the genome, transcriptome, proteome and metabolome, and the latter is considered as most representative of the phenotype. Tumors develop tumor-specific metabolism that endows them with more predominant proliferation, independent of tissue type, while retaining some metabolic traits of the tissue from which they originated. Exploring the cancer metabolome is considered as a promising way to reveal phenotypic changes related to cancer, and to establish specific biomarkers that may be used in screening for diagnostic and prognostic purposes. Many cancers have a higher cure rate if detected in early stages. Metabolomics is an analytical tool used in conjunction with pattern recognition approaches and bioinformatics to detect metabolites and follow their changes in biofluids or tissue. 1H-NMR spectroscopy and LCMS are the two major spectroscopic techniques used in metabolic analysis. This project focuses on colorectal cancer (CRC). It has been established that, apart from plasma, peripheral blood mononuclear cells (PBMC) may provide potential prognostic biomarkers for disease, and may constitute an excellent starting point for early CRC biomarker discovery. Therefore, the main objective of this project is the metabolomics analysis by 1H-NMR and LCMS of plasma and PBMC from diagnosed CRC patients in various stages and healthy controls, and to establish a set of early biomarkers for this cancer type.

Researcher(s)

• Promoter: Apers Sandra
• Promoter: Pieters Luc
• Co-promoter: Lemière Filip
• Co-promoter: Peeters Marc
• Co-promoter: Pieters Luc
• Fellow: Custers Deborah

Research team(s)

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

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

The development of metastases is by far the leading cause of death in patients with cancer, also in patients with breast cancer. Due to advances in the medical treatment of cancer, an ever-growing group of patients with metastases is eligible for treatment with so-called targeted medicines that can significantly extend survival. The effectiveness of these drugs depends in many cases to a significant extent on the presence of specific properties of the cancer cells, which often occur only in part of the patients. Moreover, these medicines - just like classical chemotherapy - can cause unpleasant side effects and their use is associated with high health care costs. Being able to demonstrate properties on cancer cells that can predict which patients will and will not respond to targeted treatment, such as endocrine therapy, is therefore of great importance to be able to use these resources responsibly. Research has shown that the presence or absence of these properties can change with time as the tumor evolves, causing people to develop resistance to treatment. This research will investigate to what extent cancer cells isolated from blood samples from patients with a metastatic form of breast cancer can be used to investigate the properties of the cancer cells at a certain moment in time, and thus to be able to predict which targeted therapies the patient will or will not benefit. The ability to carry out such research on a blood sample has the main advantages that the test can be repeated easily and frequently and is little or no burden on the patient. In this way, such a blood test may play an important role in a more personalized cancer medicine and ultimately a better treatment of patients with a metastatic form of cancer.

Researcher(s)

• Promoter: Peeters Marc

Research team(s)

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)

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
• Co-promoter: Van Camp Guy
• Fellow: Brouwer Aaltje

Research team(s)

Project type(s)

• Research Project

Abstract

The introduction of targeted therapies is now at the forefront of personalised medicine in cancer treatment. However, after the initial promise of targeted therapies, drug resistance is emerging as the major obstacle to progress in this field. In the proposed project, we will focus on unravelling and overcoming intrinsic and acquired resistance to cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Hereby, we will concentrate specifically on two highly relevant tumour types with poor prognosis, i.e. head and neck squamous carcinoma (HNSCC) and colorectal cancer (CRC). We will be the first to unravel drug resistant mechanisms and identify functional biomarkers by tumour kinome profiling. Using state-of-the-art PamGene technology, microarrays with kinase peptide substrates, mainly representing tyrosine residues, will be applied to analyse cetuximab-sensitive versus -resistant (intrinsic and acquired) HNSCC and CRC cell lines. As such, kinase activity (rather than presence) will be analysed, which is crucial to elucidate the underlying signal transduction pathways responsible for drug resistance. Afterwards, the in vitro kinase signature predicting intrinsic/acquired cetuximab resistance will be validated using HNSCC and CRC tumour patient material. Importantly, unravelling the molecular pathways underlying cetuximab resistance could have important implications not only regarding patient selection, but also regarding identification of new drug targets. Based on results from the above-mentioned kinome profiling, new (combination) treatments can be designed to overcome cetuximab resistance. In addition, the ongoing challenge of therapy resistance has already prompted a new approach to treat cancer patients, notably multiple inhibition of ErbB receptors simultaneously or irreversible inhibition, for example with the highly innovative, dual targeting agents afatinib and MEHD7945A. The molecular pathways underlying the cytotoxic effects of the selected compounds, either as monotherapy or 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, the strength of the proposed project lies in our multidisciplinary approach of drug resistance. The proposed model offers an attractive platform to investigate therapy resistance and action mechanisms of additional molecular targeted agents.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Wouters An
• Fellow: De Pauw Ines

Research team(s)

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)

Project type(s)

• Research Project

Abstract

The objective of this research project is to evaluate the clinical significance of mutation analysis on circulating free DNA and circulating tumour cells (CTC), shedded directly from the actually present tumour mass into the bloodstream, as an alternative for the archival tumour biopsy in patients with KRAS wild type mCRC.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Deschoolmeester Vanessa
• Co-promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

With this phase I/II clinical study in newly diagnosed GBM patients, we want to evaluate our in-house developed immunotherapy with Wilms' tumor 1 (WT1) messenger ribonucleic acid (mRNA)-loaded autologous dendritic cells (DCs) in combination with adjuvant temozolomide chemotherapy, following maximal, safe surgical resection and temozolomide-based chemoradiation.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Specenier Pol

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Peeters Marc
• Fellow: Boeckx Nele

Research team(s)

Project type(s)

• Research Project

Abstract

Neuroendocrine tumors (NET) form a heterogeneous group of malignancies. The phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway has been demonstrated to play a major role in NET by regulating cell growth, proliferation, cell survival and protein synthesis ). Furthermore, alterations in genes regulating this pathway are reported in pancreatic NET (PNET). Furthermore, elevated mTOR expression and activity is associated with a higher proliferative capacity and worse prognosis. mTOR proves to be an interesting target for therapy of NET with mTOR-inhibiting rapamycin and analogs (rapalogs) such as everolimus. mTOR acts as the catalytic subunit of two functionally distinct complexes, named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Although effectively blocking mTORC1, rapalogs only have a limited, dose-dependent action on the mTORC2. Recent phase III trials with everolimus show an improved progression-free survival in monotherapy in progressive advanced pancreatic NET and in combination with long-acting octreotide in advanced carcinoid tumors. However, adaptive resistance to mTOR inhibition with rapalogs is described. This adaptive resistance may be caused by induction of activating phosphorylation of Akt, upstream of mTOR in the PI3K-Akt-mTOR pathway. The effect of rapalogs on mTOR signaling may be circumvented through increased activity of mTORC2 and this may lead to resistance to rapalogs. The first aim (WP 1) of the project is to investigate the resistance mechanisms that play a key role in adaptation to everolimus treatment in PNET. To accomplish this, in vitro transcription and phosphorylation of the components of the PI3K-Akt-mTOR pathway will be studied in sensitive and secondary resistant PNET cell lines. For the transcription studies, gene expression microarrays will be performed on RNA extracted from the cell lines that are sensitive and the ones with induced (secondary) resistance. The role of Akt phosphorylation by reduced inhibition of S6K1-IRS-IGF axis and other possible unknown feedback loops will be evaluated with the western blotting. The second aim (WP 2) of the project is to determine whether DNA methylation of genes and promoter regions associated with the mTOR pathway play a role in adaptive resistance to everolimus. Therefore the DNA methylation status of sensitive and secondary resistant PNET cell lines will be studied using Illumina's Infinium methylation 450k beadchip microarrays. These methylation microarray data will be integrated with the transcription microarray data to identify functional methylation pattern changes. In patient material, important epigenetic changes, identified in the cell lines, will be quantified with pyrosequencing and will be correlated with gene expression, studied with real time PCR. Furthermore, this will be correlated to resistance to everolimus in a retrospective study with the goal of describing predictive biomarkers for response to therapy with everolimus. The third aim (WP 3) of the project is to evaluate if dual inhibition of mTOR and interesting therapeutic targets (such as IGF, PI3K, mTORC2, EGFR), which will be identified in the first parts of this research project, might overcome acquired resistance to everolimus. The role of the transcription and phosphorylation of the PI3K-Akt-mTOR pathway during dual inhibition will be studied in vitro in sensitive and secondary resistant PNET cell lines. An in vivo experiment using an orthotopic PNET cancer model, comparing dual inhibition to, respectively, placebo, mTOR inhibition alone and inhibition of the identified therapeutic targets alone will be conducted. Response will be evaluated using microPET/CT. Ex vivo studies using immunohistochemistry, real time PCR and western blotting will be used to the dual inhibition to activation of the PI3K-Akt-mTOR pathway.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Op de Beeck Ken
• Co-promoter: Pauwels Patrick

Research team(s)

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
• Co-promoter: Peeters Marc
• Co-promoter: Wouters An
• Fellow: Van den Bossche Jolien

Research team(s)

Project type(s)

• Research Project

Abstract

Pancreatic cancer is characterized by a poor prognosis and shows an almost inevitable mortality. It is shown that the tumor microenvironment, mainly the stroma around the tumor, which can constitute up to 80% of the tumor mass, would facilitate the rapid progress of pancreatic cancer. The precise role of this stroma as well as his contribution to tumor progression and therapeutic resistance is still poorly understood in pancreatic cancer and other solid tumors. This in vitro study aims at elucidating the presence and functional impact of critical components of the stroma, which can affect the behavior of pancreatic tumor cells.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Deschoolmeester Vanessa
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Fellow: Quix Céline

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we specifically wish to focus on two highly relevant tumour types, non-small cell lung cancer and pancreatic cancer. Firstly, the clinicopathological significance of Plk1 expression as a prognostic marker will be evaluated in a retrospective study investigating Plk1 gene amplification, Plk1 mRNA and protein expression. Secondly, the integration of a small-molecule Plk1 inhibitor with radiotherapy and chemotherapeutic agents for improving chemoradiation protocols will be studied. The interactions and underlying molecular biological pathways (p53 status, cell cycle progression, apoptosis, DNA repair, hypoxia-related signalling) will be investigated under both normal and reduced oxygen conditions, in parallel in an in vitro and in vivo setting. Elucidating these mechanisms could enable us to individually tailor the use of molecular targeted drugs in order to fully utilise their high potential in cancer therapy. Moreover, the proposed model offers an attractive platform to investigate the interactions and action mechanisms of additional molecular targeted agents in combination with chemoradation.

Researcher(s)

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

Research team(s)

Project type(s)

• Research Project

Abstract

The detection of minimal disease in blood of patients with cancer is hampered by a lack of sensitivity and accuracy of the currently available tests. The availability of the real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and the possibility to measure the expression of multiple genes simultaneously has initiated some change in this area. In previous research we showed a superior sensitivity of qRT-PCR for CK-19/MAM compared to immunocytochemistry for the detection of disseminated tumor cells (DTCs) in bone marrow and to the FDA approved CellSearch System (Veridex, Raritan, NJ) for the detection of circulating tumor cells (CTCs) in peripheral blood. Through the molecular characterization of CTCs in patients with metastatic breast cancer, this project aims to identify a set of markers that can be used to further enhance the sensitivity of the currently available qRT-PCR test. In addition, characterization of CTCs can improve our insight in the pathogenesis of cancer metastasis. By comparison of the gene expression profiles of blood samples enriched for CTCs and the residual CTC-depleted blood samples, a CTC-specific genome-wide gene expression profile will be generated. Crossvalidation of these discriminatory genes will be done on the primary tumor. Using discriminant analysis with the expression profile of healthy volunteers, an optimization of the amount of markers and their expression level will be determined to achieve a zero misclassification of healthy volunteers (sensitivity 100%) and an as correct as possible classification of patients with breast cancer.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Pauwels Patrick
• Fellow: Peeters Dieter

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Stroobants Sigrid
• Co-promoter: Peeters Marc
• Co-promoter: Sijbers Jan
• Co-promoter: Staelens Steven
• Co-promoter: Van Der Linden Annemie

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to develop a next generation sequencing (NGS) platform to advance in a collaborative way biological and medical research within the Antwerp research community. The consortium involves more than 16 research groups in various disciplines of medicine, biology and biomedical informatics. The goals are to identify new genes and mutations in various rare Mendelian disorders, to achieve more insights in the genetic causes of cancer and to unravel more precisely the genetic determinants of infectious diseases. This new knowledge will improve both the diagnosis and management of these human diseases. The project will also focus on the interaction between environment and genes. More specifically, the effect of environmental stressors on genetic variation in aquatic organisms, the effect of teratogenic factors on embryonic development in vertebrates and the effects of environmental conditions on growth in maize and Arabidopsis lines will be studied. The analysis of the large amount of genomic and transcriptomic data, generated by the various research groups, will be coordinated by the recently founded UZA/UA bioinformatics group Biomina

Researcher(s)

• Promoter: Mortier Geert
• Co-promoter: Beemster Gerrit
• Co-promoter: Blust Ronny
• Co-promoter: Goossens Herman
• Co-promoter: Knapen Dries
• Co-promoter: Laukens Kris
• Co-promoter: Peeters Marc
• Co-promoter: Van Hul Wim
• Co-promoter: Vrints Christiaan

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Peeters Marc

Research team(s)

Project type(s)

• Research Project

Abstract

Human papillomavirus (HPV) is responsible for approximately 25% of head and neck cancer (HNC) worldwide and appears to be associated with a better response to treatment and improved prognosis. Evidence suggests that HPV-induced HNC has steadily increased in the USA and some European countries in the last decades. However, whether this is a worldwide phenomenon and specific risk factors are associated with it remains to be proven. In addition, little is known on the natural history and risk factors of oral HPV infection. HPV-AHEAD network aims to address these and other unanswered questions on HNC etiology and epidemiology with a focus on the role of HPV.

Researcher(s)

• Promoter: Bogers John-Paul
• Co-promoter: Arbyn Marc
• Co-promoter: Peeters Marc

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

The aim of this project is to further develop uPA probes, of which we already showed the efficacy in in vitro studies, to be used in cellular and in vivo. The IP of these innovative probes have recently been submitted to the UA interface for patenting. The first step in the valorisation of the probes is to obtain proof of concept in in vivo disease models. In the subsequent phase these results will permit us to obtain further funding from larger public (Fournier-Majoie, IWT) or private (VC) institutions. Our goal is to proceed with spinning-out this te chnology into a company preferentially within 3 years.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Bogers John-Paul
• Co-promoter: De Visscher Geofrey
• Co-promoter: Joossens Jurgen
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Stroobants Sigrid
• Co-promoter: Van Der Linden Annemie

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

In a first work package, the combination with other conventional therapies as well as anti-metastatic effects and the influence on the angiogenic pathway will be studied. A second work package will determine the metabolic stability of the inhibitors and the possible presence of toxic metabolites. A third work package is necessary to provide enough material for the different test systems and will transform the uPA inhibitors to imaging probes. In a fourth work package, the effect of the uPA inhibitors will be evaluated in a primary and a metastatic tumour model. This project will determine whether these selective and potent irreversible inhibitors can be used for the development of a new therapy and/or as a chemical tool for biomarker/bio-imaging research.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Augustyns Koen
• Co-promoter: Peeters Marc
• Co-promoter: Stroobants Sigrid

Research team(s)

Project type(s)

• Research Project

Abstract

The Wilms' tumor 1 (WTI) protein has been shown to be a universal tumor antigen overexpressed in many tumors, including malignant mesothelioma and breast carcinoma. In view of the T cell immunogenicity of WTI-derived peptides, immunostimulatory dendritic cells loaded with WT1 antigen hold promise as a universal, yet patient-specific, polyepitope cancer vaccine to treat residual disease. Here, autologous monocyte-derived dendritic cells will be transfected with mRNA coding for the entire WT1 antigen and injected intradermally as a cellular cancer vaccine in mesothelioma and breast cancer patients as adjuvant treatment after optimal debulking or after neo-adjuvant chemotherapy. In this project, we want to investigate the safety, feasibility and immunogenicity of such WTI-targeted cancer vaccine in an open-label phase I trial.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Germonpre Paul
• Co-promoter: Huizing Manon
• Co-promoter: Peeters Marc
• Co-promoter: Van de Velde Ann
• Co-promoter: Van Schil Paul
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

The detection of minimal disease in blood of patients with cancer is hampered by a lack of sensitivity and accuracy of the currently available tests. The availability of the real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and the possibility to measure the expression of multiple genes simultaneously has initiated some change in this area. In previous research we showed a superior sensitivity of qRT-PCR for CK-19/MAM compared to immunocytochemistry for the detection of disseminated tumor cells (DTCs) in bone marrow and to the FDA approved CellSearch System (Veridex, Raritan, NJ) for the detection of circulating tumor cells (CTCs) in peripheral blood. Through the molecular characterization of CTCs in patients with metastatic breast cancer, this project aims to identify a set of markers that can be used to further enhance the sensitivity of the currently available qRT-PCR test. In addition, characterization of CTCs can improve our insight in the pathogenesis of cancer metastasis. By comparison of the gene expression profiles of blood samples enriched for CTCs and the residual CTC-depleted blood samples, a CTC-specific genome-wide gene expression profile will be generated. Crossvalidation of these discriminatory genes will be done on the primary tumor. Using discriminant analysis with the expression profile of healthy volunteers, an optimization of the amount of markers and their expression level will be determined to achieve a zero misclassification of healthy volunteers (sensitivity 100%) and an as correct as possible classification of patients with breast cancer.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Fellow: Peeters Dieter

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Pauwels Patrick
• Promoter: Van Marck Eric
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc

Research team(s)

Project type(s)

• Research Project