SP8: Understanding adaptation to immunotherapy in biliary cancer

Bile duct cancers are highly aggressive malignancies with limited response to systemic therapies. A subset of patients with bile duct cancer harbors a pathogenic mutation in the BRAF oncogene, that is amenable to targeted therapies. If treated with targeted inhibitors, the patients often respond, but the duration of response is limited. In SP8, we use murine models to better understand i) how tumor cells manage to survive under therapy, as well as ii) whether and how the immune system plays a role in the treatment response, and in shaping the “drug tolerant” state.

Anna Saborowski’s group is focused on the preclinical annotation of therapy resistance in biliary cancers, while Friedrich Feuerhake’s work capitalizes on innovative digital image annotation techniques and digital pathology.

Joining forces, we aim to uncover the functional relevance of cancer cell-intrinsic vs. microenvironmental determinants of drug response. In this regard, The PhD- and MD- candidates of the first cohort (Saborowski lab) will delineate the phenotypic and molecular features of the drug tolerant state in the presence vs absence of an intact immune system in a murine model by integrating RNA-, epigenetic, and proteomic analyses. Building on these data, the second cohort of trainees (Feuerhake group)will address qualitative and quantitative dynamic changes in the immune cell populations and interaction with the tumor cells, leveraging AI-supported analyses of image- and transcriptome-based patterns of immune adaptation and remodeling of the TME. We expect that through the proposed work we will identify novel vulnerabilities that pave the way towards informed therapeutic combinations for patients with biliary cancers.