Optimizing molecular and immunotherapies for the treatment of cholangiocarinoma

• Applicant: Professor Dr. Arndt Vogel
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 348083549

Cancers of the biliary system (BTC) are highly aggressive tumors with a median survival of only 11 - 13 months under systemic palliative therapy. To date, all studies that employed molecular therapies in unselected BTC cohorts were negative. In recent years, a detailed characterization of the molecular landscape of biliary tumors has been conducted and revealed that BTCs are a genetically heterogeneous group of malignancies. However, these studies also identified a subset of recurrent and targetable genetic alterations. One of the most frequent genetic alterations are mutations in the IDH1 gene, which can be found in 10-20% of patients with intrahepatic CCA, and the mIDH1 inhibitor ivosidenib has shown clinical efficacy in the Claridhy phase-III study. Critical assessment of the study however revealed that even in this genetically defined BTC patients only a subgroup of patients achieves a clinically meaningful long-term response. This observation indicates that the presence of genetic alterations does not necessarily guarantee sensitivity to targeted inhibitors, and points towards the existence of strong molecular networks that are capable of conferring primary resistance. In the near future, the field will likely move towards combination approaches, which requires a better understanding of the oncogenic pathways of the druggable genetic alterations. Therefore, the main aim of this proposal is to take this clinical observation back the “bench” and to address them with our preclinical mouse models and our clinical cohorts of iCCA patients. The main goal of this proposal is to characterize the role of mIDH1 in more detail in order to optimize its therapeutic potential. In WP 1, we will determine the influence of mIDH1 on lineage commitment in liver tumorigenesis and dissect the influence of the co-mutational spectrum on tumorigenesis and therapy response. In WP 2, we aim to understand the “direct” vs. the 2-HG mediated effects of mutant IDH through the characterization of downstream signaling and remodeling of the epigenetic landscape as well as the identification of mIDH1 binding partners. In WP 3, we will analyze how mIDH1 regulates the immune tumor microenvironment (TME) and the therapeutic potential of a combined checkpoint and mIDH1 inhibition in BTC. Finally, we will continue our ongoing efforts to establish a representative biobank of primary human patient derived cell lines and xenografts that represent our local CCA patient population.

• DFG Programme: Research Grants