Experimental GI Oncology Lab
Oncogene targeting in GI cancers
Therapeutic targeting of driver oncogenes has been a major success in clinical oncology. In the field of GI Cancers, recent advances in molecular profiling, together with the development of novel compounds targeting BRAF and, more recently, KRAS oncogenes have opened up new possibilities for personalized treatment. Our research aims to advance precision treatment in the clinic and, in parallel, model targeted treatment in the lab, employing patient-derived disease models.
Objectives of PARTACER-Suisse. Paired tissue, blood, and stool samples, will be prospectively collected from 30 patients with BRAF V600E-mutated mCRC undergoing molecularly targeted treatment with encorafenib/cetuximab, and will undergo comprehensive molecular analyses to uncover the full molecular landscape of acquired resistance to targeted treatment in this setting (Aim 1). Patient-derived organoid cultures (PDOs) will be established from tissue biopsies prior to and after treatment, validated, and employed for modeling acquired resistance in vitro (Aim 2). PDOs will be employed to establish novel strategies to prevent, delay, modify, or overcome acquired resistance. Established cell lines will serve as controls (Aim 3). By addressing these aims, PARTACER-Suisse will significantly advance the field of mCRC treatment, generating generalizable knowledge for precision oncology. Figure generated with BioRender.
Acquired resistance to targeted treatment
A major clinical limitation to the successful targeting of cancer oncogenes is the emergence of acquired resistance in patients. For instance, clinical responses to novel KRAS inhibitors or BRAF inhibitor combinations in GI cancers have proven rather short-lived, limited by rapidly emerging resistance, which is often polyclonal. A key objective of our research is to better understand the molecular mechanisms of acquired resistance in these tumors and to work out strategies for how to delay, modify, and overcome acquired resistance in GI cancers.
Schematic representation of the PARTACER-Suisse study workflow. The study will prospectively enroll patients with confirmed BRAF V600E mutated mCRC prior to molecularly targeted treatment with CE. For the clinical part of the study, paired tissue and liquid samples will be analyzed by targeted DNA NGS, and a comparative research report will be reported back to the recruiting site. For the translational part, tissues and liquid biopsies will undergo comprehensive molecular analysis. PDO established from pre-and post-treatment biopsies will be exploited for treatment modeling in vitro. Figure generated with BioRender.
Molecular response monitoring
Another key focus of the lab is to develop and employ molecular monitoring tools for cancer patients undergoing cancer treatment. We establish digital PCR multiplex panels for the analysis of cell-free, tumor-derived DNA based on an individual`s tumor molecular profile (tumor-informed panels). With these panels, we perform longitudinal analysis of patient plasma and find ctDNA dynamics to be highly predictive of clinical outcomes. The next steps are to prospectively employ these panels in interventional clinical trials.
Organoid modelling
Patient-derived tumor organoids (PDOs) are 3D tumor cultures growing in matrix. PDOs retain genotype and much of the phenotype of individual patient tumors. In the lab, we have established protocols to derive PDOs from colorectal and pancreatic cancers with a very high success rate. We employ these cultures to study tumor biology, model treatment and explore treatment resistance. In parallel, we employ established cell lines for drug and genetic screenings.
(A) Schematic representation of the pipeline for the establishment of patient-derived colon cancer organoids. Figure generated with BioRender. (B) Examples of patient-derived colon cancer organoids derived in our laboratory under phase contrast (left) and stained with DAPI (blue), actin (red), and E-Cadherin (green). (C) Digital droplet PCR (ddPCR) analysis of tissue (head) and organoid DNA (bottom) for estimation of tumor cell content according to variant allele frequency (VAF) and to control for culture drift.