Oncogenetics

Improving colorectal cancer detection and treatment follow-up through the development of a novel methylation assay.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide and is ranked second in terms of mortality. The current gold standards for follow-up of CRC (CT imaging and tumor markers) have important drawbacks. In light of these limitations, there is a need for a new, non-invasive and accurate technique. Preliminary data has shown that quantification of NPY methylation in plasma samples is a promising technique for follow-up of metastatic CRC patients. The advantage of this technique is that plasma samples can be acquired minimally invasive and that this technique is suitable for all colorectal cancer patients (regardless of the mutational profile of the tumor).

In order to study whether NPY methylation analysis in plasma samples can be used to guide treatment in metastatic CRC, we will conduct the FOLICOLOR trial. This is a prospective multicentre trial in which we will first investigate whether NPY methylation can be used to detect progressive disease earlier than standard follow-up based on CT imaging and later whether adapting treatment based on NPY methylation analysis can improve progression-free survival and quality of life.

PhD student: Katleen Janssens
Supervisors: Ken Op de Beeck, Guy Van Camp & 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

Screening and early detection of colorectal cancer and breast cancer in liquid biopsies using a newly-developed multi-regional methylation assay.

Colorectal cancer and breast cancer are amongst the most common and deathliest cancers world-wide. Screening programs in Flanders still encounter important limitations such as limited sensitivity, invasiveness, and moderate participation rates. Therefore, we propose a new, blood-based screening test using our newly developed technology. This novel technology can achieve higher sensitivity and specificity compared to existing techniques, due to the detection of multiple DNA methylation markers simultaneously and the circumvention of harsh chemical conditions (bisulfite treatment). By investigating DNA methylation of early developmental stages of tumors, for example polyps in the colon, we aim to discover biomarkers that can identify cancer in its earliest stages. In summary, with this project, we investigate the possibility to discriminate colorectal and breast cancer in early stages from healthy samples using only a blood sample.

PhD student: Isabelle Neefs
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.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide and is ranked second in terms of mortality. The current gold standards for follow-up of CRC (CT imaging and tumor markers) have important drawbacks. In light of these limitations, there is a need for a new, non-invasive and accurate technique. Preliminary data has shown that quantification of NPY methylation in plasma samples is a promising technique for follow-up of metastatic CRC patients. The advantage of this technique is that plasma samples can be acquired minimally invasive and that this technique is suitable for all colorectal cancer patients (regardless of the mutational profile of the tumor).

In order to study whether NPY methylation analysis in plasma samples can be used to guide treatment in metastatic CRC, we will conduct the FOLICOLOR trial. This is a prospective multicentre trial in which we will first investigate whether NPY methylation can be used to detect progressive disease earlier than standard follow-up based on CT imaging and later whether adapting treatment based on NPY methylation analysis can improve progression-free survival and quality of life.

PhD student: Joe Ibrahim
Supervisors: Guy Van Camp, Severien Van Keer, & Ken Op de Beeck
Supervisor: Alex Vorsters .

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

Leveraging patient-driven research to improve rational therapy selection in ROS1+ non-small cell lung cancer (NSCLC).

ROS1+ non-small cell lung cancer accounts for ~ 2% of newly diagnosed cases. Despite the recent identification of this new molecular subset, targeted therapies by using tyrosine kinase inhibitors have been approved, leading to an initial outstanding response after treatment. However, diverse mechanisms of resistance to overcome ROS1 kinase inhibition have been reported in patients who relapse. Among the most frequent de novo mutations acquired by tumor cells, point mutations affecting kinase domain that impair drug binding are an important therapeutical challenge to overcome. In this project, we combine computational protein modelling and simulations to explore protein dynamics of wild type and mutant ROS1 kinase domain. Combination with in-vitro genetic engineering tools to establish patient-derived ROS1+ NSCLC cell lines will gain more detailed insights about mutations. Eventually, we aim to offer a more representative, standardized pre-clinical experimental model that will help to rationalize therapy selection upon the detection of de novo mutations during disease progression.

PhD student: Farhan Ul Haq
Supervisors: Guy Van Camp, Ken Op de Beeck, Geert Vandeweyer & Patrick Pauwels

Bioinformatics analysis of large datasets for detection of genetic and epigenetic tumor signatures of lung and colorectal cancer.

In 2020, approximately 19.3 million people got a new cancer diagnosis, and 9.9 million people died from cancer. A factor that plays a huge role in patient prognosis is the cancer stage: the earlier a tumour is treated, the better. Therefore, we aim to develop a new assay for early cancer detection and follow-up by analysing differential methylation of specific CpG sites in the genome. For this project, previously reported CpG sites were used, found by our lab. Building on these results, my work is twofold: first, I do the data analysis of the sequencing data that we generate of our own samples, analysed with our novel technique. This consists of writing and updating the analysis pipeline, quality control and statistical modelling. Secondly, I am validating the previously found results with online datasets from another type of methylation data: Whole-genome bisulfite sequencing. Our next step is to use the assay in liquid biopsies, for minimally invasive testing.

PhD student: Thomas Vanpoucke
Supervisors: Guy Van Camp, Ken Op de Beeck, & Marc Peeters

Leveraging patient-driven research to improve rational therapy selection in ROS1+ non-small cell lung cancer.

ROS1+ non-small cell lung cancer accounts for ~ 2% of newly diagnosed cases. Despite the recent identification of this new molecular subset, targeted therapies by using tyrosine kinase inhibitors have been approved, leading to an initial outstanding response after treatment. However, diverse mechanisms of resistance to overcome ROS1 kinase inhibition have been reported in patients who relapse. Among the most frequent de novo mutations acquired by tumor cells, point mutations affecting kinase domain that impair drug binding are an important therapeutical challenge to overcome. In this project, we combine computational protein modelling and simulations to explore protein dynamics of wild type and mutant ROS1 kinase domain. Combination with in-vitro genetic engineering tools to establish patient-derived ROS1+ NSCLC cell lines will gain more detailed insights about mutations. Eventually, we aim to offer a more representative, standardized pre-clinical experimental model that will help to rationalize therapy selection upon the detection of de novo mutations during disease progression.

PhD student: Marc Terrones
Supervisors: Guy Van Camp, Ken Op de Beeck & Geert Vandeweyer

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

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

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.