Abstract PO-014: DNA methyltransferases drive gastric cancer growth and present a therapy target for gastric cancer

Abstract

Abstract Gastric cancer (GC) remains the third leading cause of cancer related death worldwide. While inflammation is a well-established driver of gastric tumorigenesis, only a small subset of GC patients responds to immunotherapy. The understanding of the tumor microenvironment, which suppresses anti-tumor immune responses, is a field of great interest. One proposed mechanism of immune escape is silencing tumor antigen expression by DNA methylation, and thereby avoiding immune recognition. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and hence, for the epigenetic silencing of gene expression of tumor antigens and other immune related molecules. DNMTs are often overexpressed in solid tumors. Epigenetic drugs inhibiting these DNMTs have shown anti-tumor effects in combination with immune checkpoint inhibitors by re-activating the expression of tumor antigens, amongst others. Here we are studying the role of DNMTs in GC mouse models and the possibility of combining DNMT inhibitors with immunotherapy for the treatment of GC. This project utilizes various mouse models of GC. The Gp130Y757F/Y757F (gp130FF) mutant mouse model develops spontaneous inflammation driven gastric adenomas. We established a gp130FF Dnmt3a overexpressing gastric cancer mouse model (gp130FF, A33Dnmt3a) where Dnmt3a overexpression occurs in gastric tumors. In a second mouse model, mutant Kras, Pi3kca and Tp53 expression results in highly advanced invasive gastric carcinoma formation (KPT model). We successfully established gastric cancer organoids of one of these triple mutant tumors (KPT organoids) which can be injected subcutaneously into wild type mice and result in allograft tumor formation. DNMT3A overexpression was detected in human GC specimen and associated with bad overall survival of patients. Gastric adenomas of our (gp130FF, A33Dnmt3a mouse model have a 10-fold elevated Dnmt3a expression. Importantly, tumor specific Dnmt3a overexpression significantly increased gastric tumor burden. In the KPT model, we have identified DNMT3A as being highly expressed in the invasive front of tumors, their liver metastases as well as in the allograft tumors established by the KPT organoids. In this model of advanced gastric cancer, treatment with the DNMT inhibitor decitabine significantly decreased tumor growth and we are currently investigating the efficacy of decitabine in combination with anti PD 1 immunotherapy. Taken together, we provide evidence for a driver function of Dnmt3a in gastric tumorigenesis and gastric tumor growth. In addition, we demonstrate the vulnerability of an aggressive gastric carcinoma model to DNMT inhibition and hence its non-oncogene addiction to DNMTs. Therefore, our findings encourage further studies to investigate the potential of DNMT inhibitors for the treatment of GC. Citation Format: Anne Huber, Christine Dijkstra, Matthias Ernst, Moritz Eissmann. DNA methyltransferases drive gastric cancer growth and present a therapy target for gastric cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-014.