Oncogenetics

Development of a biomarker test for the screening and treatment response monitoring of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is mostly diagnosed in an advanced incurable stage and therefore, there is a need for new sensitive early detection biomarkers. DNA methylation is a promising field for biomarker detection. However, no sensitive and multiplexing DNA methylation detection techniques currently exist that can detect tumor specific methylation signatures in a cost-effective manner. Therefore, we develop a novel DNA methylation detection technology in the first part of this study. This bisulfite-free technology is able to examine thousands of target regions simultaneously. In addition, we are working on an MPM specific methylation signature based on online available data and data generated in our lab. We will select differentially methylated CpG regions and validate this panel with the new technology. Eventually, we will validate the assay in MPM and healthy tissue and blood samples.

PhD student: Janah Vandenhoeck
Supervisors: Guy Van Camp, Ken Op de Beeck & Jan van Meerbeeck

Towards individualized treatment prediction and real-time follow-up of metastatic colorectal cancer patients using methylation biomarkers.

Standard treatment for patients with metastatic colorectal cancer (CRC) consists of chemotherapy combined with targeted therapy. However, the response rate to this therapy is only 30-50%, indicating the existence of unknown resistance mechanisms. Yet today, patients receive the potentially toxic targeted therapy because these resistance mechanisms have not yet been discovered and current conventional methods to detect resistance (such as radiologic imaging) are insufficiently sensitive. Therefore, new, sensitive and specific biomarkers are needed. Methylated DNA biomarkers that can predict primary therapy response and detect acquired resistance earlier than CT imaging will be identified. Two multiplexed assays using droplet digital PCR will be developed. One assay will consist of primary resistance biomarkers, with the aim of developing a prediction test on tissue. Another assay will be developed for blood, where acquired resistance biomarkers will allow real-time monitoring of patients receiving this therapy.

PhD student: Ana Regina de Abreu
Supervisors: Guy Van Camp, Ken Op de Beeck, & Marc Peeters

Improving diagnostic accuracy and follow-up of neuroendocrine neoplasms through detection of (epi)genetic biomarkers in liquid biopsies using novel technological platforms.

Neuroendocrine tumors (NETs) arise from the neuroendocrine cells in various organ systems and present with very different characteristics and vague symptoms making it extremely challenging to diagnose them. Moreover, long-term follow-up is required to monitor tumor growth and response to therapy. However, current diagnostic and follow-up strategies have several shortcomings, resulting in a high need for alternatives. Recently, we showed that circulating tumor DNA (ctDNA) is present in the blood of NET patients with metastases. This ctDNA contains the same mutations and alterations as the tumor tissue and therefore has great potential as a tumor marker. The aim of this project is therefore to determine whether the (amount of) ctDNA can serve as a suitable tumor marker for diagnosing and monitoring NET patients. For this purpose, we will use two new, highly sensitive technologies that are capable of detecting even very low amounts of ctDNA.

PhD student: Laura Mariën
Supervisors: Guy Van Camp, Ken Op de Beeck, & Marc Peeters

Developing a combined screening and molecular triage approach for cervical cancer based on HPV detection, quantification, genotyping and DNA methylation in self-samples.

In Flanders, 37% of the population eligible for cervical cancer screening is not reached by the current screening program. Here self-sampling, done at home, could pose an attractive alternative strategy for this hard-to-reach population. Infection with the human papillomavirus (HPV) is the cause of cervical cancer. Consequently, HPV detection is currently implemented as screening test. In case HPV is detected, an additional test (triage) is necessary to avoid overtreatment as the majority of HPV infections are spontaneously cleared and do not result in cervical cancer. For this triage the presence of aberrant cells in the pap smear is assessed. HPV detection performs well on self-samples, however, triage by detecting aberrant cells is not possible in this sample type. Therefore, in this project we will develop a test in which the detection of HPV and triage can be performed in one step on self-samples. As such we hope to reach more women and give them a better prediction of their cancer risk.

PhD student: Eef van den Borst
Promotors: Guy Van Camp, Severien Van Keer, Ken Op de Beeck, Wiebren Tjalma
Begeleider: Alex Vorsters

Tackling delayed diagnosis and therapy resistance in malignant pleural mesothelioma using patient-derived organoids and liquid biopsies.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor that originates in the pleura, covering the lungs, and is associated with asbestos exposure. Due to its non-specific presenting symptoms and the need for imaging or tissue biopsies, diagnosis is delayed. Moreover, relapse from current treatments is inevitable, making it palliative in intention. There is thus an urgent need for both earlier diagnosis and detection of chemotherapy resistance to improve patients’ quality of life. Therefore, in this project, I aim to construct a diagnostic and a follow-up biomarker panel based on MPM-specific molecular alterations and methylation patterns. For this, I will sequence DNA from either liquid biopsies of MPM patients or from established patient-derived organoids that mimic chemotherapy resistance in vitro. Then, using a novel highly sensitive detection technique, the two biomarker panels can be detected in circulating tumor DNA of liquid biopsies. This will improve early diagnosis and enable patient follow-up during chemotherapy, in order to reduce unnecessary toxicity and futile treatment.

PhD student: Nele De Meulenaere
Supervisors: Guy Van Camp, Ken Op de Beeck & Christophe Deben

Complex decision-making in neuroendocrine neoplasia: from germline testing to treatment sequencing

Neuroendocrine neoplasia (NEN) is a heterogeneous disease with substantial variation in genetic background, clinical behavior, and treatment response. This heterogeneity complicates both hereditary risk assessment and therapeutic decision-making.

The first part of this PhD project focuses on germline predisposition in NEN. It examines the clinical relevance of inherited genetic variation, evaluates current approaches to germline testing, and aims to better define the contribution of hereditary factors across NEN. These studies will provide a foundation for larger-scale genomic characterization within the 1000 NEN Genome Project.

The second part focuses on treatment sequencing in gastroenteropancreatic neuroendocrine tumor (GEP-NET), including the role of second-line somatostatin analogue strategies within the retroSAUNA and SAUNA trials and broader questions on sequencing of systemic treatment across different disease stages and biological trajectories.

Together, this work aims to support more genetically informed and individualized decision-making in NEN.

PhD student: Siddharth Chhajlani
Promotors: Timon Vandamme, Guy Van Camp & Ken Op de Beeck
Supervisor: Katleen Janssens

Strategic Advancement in Neuroendocrine Neoplasms: Bridging AI and Omics for Precision Oncology

The focus of my project is to explore the largely unknown territory of Neuroendocrine Neoplasms (NENs), a complex and challenging area of cancer research. Despite advances, we've only begun to scratch the surface in identifying key genes for early detection and monitoring of these cancers. This project will bridge the gap between cutting-edge machine learning techniques and biological understanding, using the latest artificial intelligence to push forward the state of the art in cancer research. We aim to develop a groundbreaking test, or assay, for NENs. This requires rigorous evaluation and benchmarking to ensure its effectiveness. Additionally, we plan to use predictive models to tailor individual patient treatments, enhancing the personalized approach to cancer care. After initial data analysis and refinement, we will process the samples through three cutting-edge biomarker detection methods. These methods will separately examine genetic fragments and DNA methylation patterns, providing fresh insights into NENs and improving our understanding of the disease. We will combine the findings from sWGS and IMPRESS to create a new set of biomarkers. This innovative approach will map DNA methylation patterns onto genetic fragments, extracting key features that reveal the underlying genetic structure of NENs.

PhD student: Vasileios Lemonidis

Promotors: Timon Vandamme, Guy Van Camp, Ken Op de Beeck, Joris Vermeesch

Begeleiders: Joe Ibrahim, Tanja Jatsenko

Guiding treatment and monitoring disease evolution in metastatic colorectal cancer through a combined methylation- and mutation-based multiplex biomarker assay in liquid biopsies

Metastatic colorectal cancer (mCRC) is the second leading cause of cancer-related death worldwide. A major challenge in its management is disease progression, often due to treatment resistance, which is typically detected too late using imaging techniques such as CT-scans. This project aims to develop a minimally-invasive liquid biopsy test to enable closer patient monitoring and timely treatment adjustments.

First, an epigenome-wide analysis will be conducted to identify novel methylation markers linked to tumor burden and resistance. These findings will be translated into an in-house developed targeted next-generation sequencing (NGS) assay, called IMPRESS. The test will be clinically validated using longitudinal blood samples from a large, well-characterized patient cohort enrolled in the ongoing phase II FOLICOLOR trial.

Within this trial, the NPY ddPCR assay is used as the current gold standard for methylation analysis in mCRC, reflecting the proportion of circulating tumor DNA in the bloodstream. The continued conduct of the FOLICOLOR trial and the generation of this extensive clinical dataset are highly valuable for patient follow-up and provide an important reference framework for the validation of the newly developed IMPRESS assay.

Ultimately, this project aims to deliver an affordable and scalable tool for personalized monitoring in mCRC, improving patient outcomes, quality of life, and reducing healthcare costs.

Phd student: Ayla Wyninckx

Promotors: Ken Op de Beeck, Guy Van Camp & Timon Vandamme

Self-samples as user-friendly liquid biopsies for early diagnosis of gynecological cancers: a methylation-based testing approach.

Gynecological cancers pose a high burden on both women and the healthcare system. Within these cancers, endometrial cancer has the highest incidence in high-income countries, ovarian cancer is the most lethal, and vulvar cancer is susceptible to less awareness and more shame. Unfortunately, these cancers are either asymptomatic or present with unspecific symptoms, blocking early diagnosis and leading to poor prognosis. In addition, current diagnostic methods are costly with suboptimal accuracy or patient discomfort. This emphasizes the need for a new user-friendly diagnostic test to detect gynecological cancers in an earlier stage. This way, the prognosis of women can be improved and the costs for the healthcare system reduced. Previous research has shown the potential of DNA methylation as a biomarker for cervical cancer detection in self-samples (i.e., first-void urine and vaginal self-samples). DNA methylation is a universal early carcinogenic event that can be detected in self-samples. Methylation markers specific for each of the gynecological cancers will be selected and tested in (self-)samples from a patient cohort using an in-house developed methylation detection technique (IMPRESS). As such, the aim is to improve diagnostic accuracy and provide a user-friendly screening solution, reducing gynecological cancer morbidity and mortality, and healthcare costs.

PhD student: Tine Pinxteren

Promotors: Alex Vorsters, Severien Van Keer, Ken Op de Beeck

Begeleiders: Guy Van Camp, Wiebren Tjalma

Development of a blood-based multi-cancer early detection assay with tissue-of-origin profiling to guide diagnostic decision-making.

In clinical practice, many patients initially present with non-specific symptoms. At this stage, clinical suspicion is often insufficient to justify invasive procedures or extensive imaging. As a result, diagnostic trajectories are frequently prolonged, delaying definitive diagnosis and treatment initiation. These limitations highlight the critical gap in today’s diagnostic pathway, namely the absence of sensitive, minimally invasive tools capable of detecting early biological signals of cancer and supporting timely clinical decision making.
Therefore, we want to develop and evaluate a minimally invasive blood-based MCED assay. This MCED assay will be capable of identifying early biological signals of cancer and accurate determination of the tissue-of-origin for the eight most common cancer types. By integrating multi-cancer and tissue-specific DNA methylation signatures, this project aims to shorten diagnostic trajectories, guide clinical prioritisation, and support more timely and targeted follow-up investigations.

PhD student: Jana Thys
Promotors: Guy Van Camp, Ken Op de Beeck & Karen Zwaenepoel

Development of a meCUP DNA-methylation test to improve the diagnosis of cancer of unknown primary

Currently, 3 to 5% of cancer patients receive a diagnosis of Cancer of Unknown Primary (CUP), where the tissue-of-origin remains unidentified. This uncertainty contributes significantly to patient anxiety and diminishes quality of life. Treatment options are limited to empiric chemotherapy, with median survival ranging from 6 to 9 months. Therefore, there is an urgent need for a novel test to accurately determine the tissue-of-origin in CUP. This project aims to develop, optimize, validate, and implement a rapid, cost-effective test known as meCUP for precise CUP diagnosis. Initially, we will create a comprehensive DNA methylation reference atlas. Subsequently, we will model and optimize the meCUP test, validating it with biobanked samples from patients with cancers of known and unknown primary origin. Following assay optimization and validation, a non-interventional prospective trial will assess the meCUP test's integration into diagnostic workflows, supporting future interventional clinical trials. Throughout the project, we will promote awareness of CUP to enhance access to the meCUP assay for patients in Belgium. We will also identify the specific needs and concerns of CUP patients to establish a dedicated care pathway. The meCUP project holds the potential to significantly enhance CUP diagnosis by offering a more accurate, accessible, and cost-effective method for identifying the primary tumor site. This advancement could improve treatment strategies, outcomes, and overall quality of life for CUP patients.

PhD student: Jonas Dahnoun
Promotors: Karen Zwaenepoel, Léon van Kempen, Ken Op de Beeck, Guy van Camp en Senada Koljenović

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