Research Ken Op de Beeck

Abstract

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumour that is associated with asbestos exposure. Due to its non-specific presenting symptoms and the need for imaging and tissue biopsies, diagnosis of MPM is delayed, thereby negatively impacting prognosis. Moreover, relapse from current treatments (chemotherapy, immunotherapy) 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 (copy number alterations (CNAs) and differentially methylated CpG sites) that can be detected in liquid biopsies. I already successfully established a patient-derived organoid model, which will be further optimised during this project. This model will eventually be used to detect genomic and methylomic alterations associated with chemotherapy resistance. Then, using a novel highly sensitive detection technique, the two biomarker panels will be detected in circulating tumour DNA of liquid biopsies, enabling rapid and minimally invasive tumour detection. Consequently, the goal of this project is to improve early diagnosis as well as enable patient follow-up during chemotherapy, in order to reduce unnecessary toxicity and futile treatment.

Researcher(s)

• Promoter: Op de Beeck Ken
• Fellow: De Meulenaere Nele

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This SEP subsidy will contribute to a resubmission of the PhotoCan proposal in which the uptake of a new detection platform in existing population-based screening programmes in Europe is the overarching goal. PhotoCan will contribute to the screening and early detection of cancer via the electrochemical detection of cancer (epi)genetic biomarkers. Those biomarkers are increasingly discovered and validated, but the applicability in everyday medical practice requires low-cost, rapid, accurate and sensitive detection devices. To achieve this, the combined use of electrochemical detection with light-triggered sensor technology for the specific and sensitive detection of preselected cancer (epi)genetic biomarkers is proposed. The application of this technology with single and multiplexing capabilities aims to advance and integrate the technology into prototypes demonstrated in a relevant environment both for screening of colorectal cancer (high incidence) and point-of-care testing of pancreatic ductal adenocarcinoma (low incidence). Via the involvement of oncologists, lab technicians, healthcare professionals, citizens (healthy and patients), screening programmes and health policy makers, PhotoCan will address the implementation requirements from the onset, leading to maximal uptake in existing population-based screening programmes, the creation of new EU-wide screening programmes and the creation of risk-based point-of-care early detection strategies for low incidence, deadly cancers. This SEP grant will be used to appoint a scientist to 1) establish a stronger network with more partners from different EU countries, characterized by different uptake numbers in population-based screening programmes, 2) perform experiments to detect cancer (epi)genetic biomarkers to have a stronger case inviting stakeholders in the field (screening programmes) and 3) coordinate the huge efforts to come to a resubmission, also addressing the feedback from the previous submission.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy

Research team(s)

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

Project type(s)

• Research Project

Abstract

Cervical cancer is a major impact on public health, causing approximately 150 deaths in Belgium each year. Despite that there is a screening program in Flanders, 37% of the population eligible for cervical cancer screening is not reached by the current program that is based on analysing cervical smears (pap smears). Here, self-sampling, potentially done at home, could pose an alternative strategy for this hard-to-reach population. Infection with the human papillomavirus (HPV) is the cause of nearly all cervical cancer cases. 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. We will develop a test in which the detection of HPV and triage can be performed in one step on self-samples (as well as traditional cervical samples). As such we hope to reach more women and disturb less. Indeed, fewer women will need to be referred for follow-up causing less (emotional) distress. Thus, in this project we aim to reach more women in cervical cancer screening and give them a better prediction of their cancer risk.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Keer Severien

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

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

37% of the population eligible for cervical cancer screening in Flanders is not reached by the current program. Here, self-sampling could pose an alternative strategy for this hard-to-reach population. Persistent infection with the human papillomavirus (HPV) is the cause of nearly all cervical cancer cases. Consequently, HPV DNA detection is considered the superior screening test to date due to its increased sensitivity as compared to cytology. However, it is associated with a lower clinical specificity as the majority of HPV infections are spontaneously cleared and do not result in clinically relevant disease. Thereby an additional triage step is necessary to prevent over-referral and potentially overtreatment which can be done by cytology. HPV DNA-based screening can already be performed on self-samples, however, this is not the case for cytology. By developing a fully molecular, combined screen and triage approach (one-step) based on HPV DNA detection, quantification, genotyping, and DNA methylation and that can be applied on self-samples (as well as cervical samples), we will provide a solution for the current screen and triage challenges. This will avoid over referral and allow better guided management of women needing treatment, while simultaneously increasing the participation rate. As such, the morbidity and mortality of cervical cancer could be reduced and both the health of the patients as well as the costs for the healthcare system would be positively affected.

Researcher(s)

• Promoter: Vorsters Alex
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Keer Severien
• Fellow: van den Borst Eef

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

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

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

Colorectal cancer is one of the most frequent malignancy worldwide and is an important contributor to cancer related deaths. The standard first-line therapy for patients with metastatic colorectal cancer (mCRC) is a cytotoxic doublet combined with targeted therapy (anti-EGFR). Sadly, not all patients show good responses to this therapy. RAS mutational status is a known predictive biomarker for response to anti-EGFR therapy. However, even in the group of RAS WT patients, the response rate to anti-EGFR therapy is only 30-50%, indicating that there are more resistance mechanisms to be discovered. In this project, we will study primary resistance mechanisms in RAS WT mCRC patients that do not respond to anti-EGFR therapy in order to identify new predictive biomarkers. New biomarkers to predict resistance are much needed as they could spare patients from unwanted side effects from ineffective therapies, enhancing efficacy and contributing to a better quality of life. Epigenetic changes in cancer have attracted great attention in recent years. Breakthrough research of our group has shown that certain methylation patterns can be used as biomarkers in a variety of cancer types, including colorectal cancer. Sparse data even indicates that certain methylation patterns can be responsible for the variability of therapeutic responses to anti-EGFR therapy in mCRC, but this is vastly underexplored. In this project, we aim to identify new methylation biomarkers for primary resistance to anti-EGFR therapy in mCRC using methylome data. The outcome of this study could have a major impact on patient treatment.

Researcher(s)

• Promoter: Op de Beeck Ken

Research team(s)

• Center for Oncological Research (CORE)

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

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

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: Op de Beeck Ken
• Fellow: Hylebos Marieke

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

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Op de Beeck Ken

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Op de Beeck Ken

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Laer Lut
• Fellow: Op de Beeck Ken

Research team(s)

Project type(s)

• Research Project