Research Timon Vandamme

Abstract

Cholangiocarcinoma (CCA), an aggressive cancer of the epithelial cells of the bile ducts, is unfortunately often diagnosed in the late stage, leading to limited treatment options and subsequently to poor prognosis (5-year overall survival rates of 7-20%). Late-stage, unresectable disease is typically tested for FGFR2 fusions in tissue samples. However, diagnostic tissue samples often fail to capture the heterogeneity of the disease and may be inaccessible or risky to obtain. Liquid biopsies offer a promising minimally invasive alternative. While existing molecular techniques for gene fusion detection, such as FISH, RT-qPCR, and targeted RNA sequencing, have shown efficacy, they possess limitations in terms of speed, cost, multiplexing (i.e., simultaneous detection of different markers in the same sample), technical complexity and adaptability to liquid biopsies. To address these challenges, we propose a novel enzyme-free approach utilizing a singlet oxygen-based photoelectrochemical (1O2-PEC) platform for the fusion partner-agnostic detection of FGFR2 fusions in CCA patients. This platform offers high sensitivity, rapidity, ease-of-use, possibility for multiplexing, and is cost-effective. During the project, we will develop highly specific probes, evaluate their performance and determine the minimal sample preparation for tissue and liquid biopsies as a first push towards the routine clinical practice.

Researcher(s)

• Promoter: Koljenovic Senada
• Co-promoter: De Wael Karolien
• Co-promoter: Vandamme Timon
• Fellow: Arnouts Jorine

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

COVID-19, a disease caused by an infection with SARS-CoV-2, has a broad range of clinical presentations varying from asymptomatic to severe bilateral pneumonia and even death. The risk to develop severe COVID-19 as well as the mortality is the highest in the elderly and in people with a pre-existing condition such as cancer. Hence, cancer patients were prioritized for COVID-19 vaccination even though data on the effectiveness and safety was not available as immunocompromised patients, like cancer patients, were excluded from vaccine approval trials. Since the approval of different COVID-19 vaccines, our group as well as many others performed studies to map the immunological responses of cancer patients after vaccination. In general cancer patients have reduced humoral immune responses after COVID-19 vaccination, nevertheless the vaccines are well-tolerated. As COVID-19 is evolving to be an endemic virus, it is important to map all parts of the vaccination-induced immune response. While most studies report IgG levels and neutralizing antibodies when investigating the humoral immunity, IgA antibodies are important for mucosal immunity and eliminate pathogens immediately at the point of entry (e.g. respiratory system). In the context of influenza, IgA serum levels have been correlated with influenza vaccine efficacy and influenza-specific IgA has been shown to be more effective in preventing infections in mice and humans compared with influenza-specific IgG. Therefore the level of IgA in serum may serve as an indicator of host immune response and might possible be a better predictor for protection against respiratory viruses compared to IgG, but studies on IgA production upon COVID-19 vaccination are lacking. Additionally, studies assessing the role of innate immune cells in vaccination-induced immune response are scarce. A recent study provided the first hints towards the predictive capacity of NK cells -innate lymphocytes that are crucial for mediating anti-viral responses- for vaccine-induced immunity in both healthy individuals and immunocompromised patients without cancer. This is in line with other research highlighting the potential of the activity level of NK cells to serve as a biomarker for a functional immune response, but as NK cells are involved in anti-tumor responses and might be affected by anti-neoplastic treatment, it is currently unknown if these findings can be applied in a cancer population. Hence, the aim of the current study is to gain a more in depth understanding of the different aspects of vaccination-induced immunity against SARS-CoV-2 in cancer patients focusing on both IgA levels and NK cells. This will help guiding COVID-19 vaccination strategies for cancer patients during future endemic outbreaks by providing knowledge on the state of the immune system of cancer patients and their response upon vaccination. Furthermore, the obtained insights can be used to improve vaccination strategies for cancer patients for other viruses as well as when novel viral pathogens emerge.

Researcher(s)

• Promoter: Vandamme Timon
• Co-promoter: Van Audenaerde Jonas
• Fellow: Debie Yana

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Inspired by the European Union (EU) commission, this project aims to address a major societal challenge: fighting cancer. The EU has ambitious goals, such as saving more than three million lives and improving diagnosis and treatment for everyone in Europe. MutArray will contribute to achieve them by providing fast, affordable and reliable diagnosis and monitoring for colorectal cancer (CRC), which is the second leading cause of cancer deaths globally. Accurate detection of clinical biomarkers is a priority, requiring analytical devices that enable rapid analysis with high specificity and sensitivity. Electrochemical bioplatforms are emerging tools for diagnostic systems thanks to their inherent simplicity, cost and time effectiveness, which are the limitations of current clinical technologies. MutArray will focus on the development of a 96-well plate multiplexed bioplatform based on the use of the singlet oxygen-mediated photoelectrochemistry, locked nucleic acids (LNA) probes and the CRISPR/Cas system for the specific detection of CRC biomarkers, such as single nucleotide variations (SNVs). Both solid (tissue) and liquid (plasma) biopsies from CRC patients will be analyzed and clinically validated for SNV detection in the KRAS oncogene. This novel approach can be used to detect any nucleic acid biomarker and will ensure the translation from a laboratory technology to a benchtop device for clinicians and hospital settings that positively impacts the fight against cancer.

Researcher(s)

• Promoter: De Wael Karolien
• Co-promoter: Vandamme Timon
• Fellow: Valverde De La Fuente Alejandro

Research team(s)

• Antwerp engineering, PhotoElectroChemistry & Sensing (A-PECS)

Project type(s)

• Research Project

Abstract

T-cells are not only crucial actors in our defense against microbes but play an important role in protecting us from cancer. T-cells recognize their targets via its T-cell Receptor (TCR), which consists of a TCRa and TCRb chain. It has been shown that the cancer tissue TCR repertoire holds capacity in predicting which cancer patients will respond to checkpoint-inhibitor therapy, thereby supporting the concept that the tissue-specific TCR repertoire may be considered a stratification biomarker. Decoding the paired TCRab repertoire from the routinely obtained FFPE tissue, necessitates the development of a new single cell workflow method that will allow FFPE tissue paired TCRab sequencing. This would potentially represent a revolution, not only in oncology, but in autoimmunity diseases too where rogue Tcells could be found in affected tissues. In this project, we will create, develop and validate an experimental protocol to obtain paired TCRab data from FFPE tissue.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Vandamme Timon

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Neuroendocrine neoplasms (NENs) require regular assessment of tumor growth and treatment response. However, adequate, non-invasive tumor markers are currently lacking. Recently, we demonstrated that sequential genome-wide copy number alteration (CNA) profiling of circulating cell-free DNA (ccfDNA) could serve as novel, non-invasive biomarker in NEN patients. Expanding upon these findings, we will explore and benchmark a new analytical approach, GIPXplore, against the current gold standard for ccfDNA CNA analysis (ichorCNA). Moreover, aberrant methylation in ccfDNA will be analyzed using the novel, highly sensitive MSRE-smMIP-seq technology. Both methods for detection and quantification of tumoral DNA will be correlated to clinical outcomes in an extensive prospectively collected cohort of 250 NEN patients. This cohort will be established through the international collaboration between the Belgian ENETS CoEs and Dutch FORCE initiative. In doing so, we will validate the potential added value of ccfDNA analysis for clinical decision-making in NEN patients and facilitate clinical implementation.

Researcher(s)

• Promoter: Vandamme Timon

Research team(s)

• Center for Oncological Research (CORE)

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 has a direct impact on patients' lives. Over the past few years, liquid biopsies have gained interest as a minimallyinvasive 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 cellfree 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 not capable 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: Vandamme Timon
• Fellow: Vandamme Timon

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project