Flash Talk & E-Poster Presentation 33rd Lorne Cancer Conference 2021

DNA methyltransferases drive gastric cancer growth and present a therapy target for gastric cancer (#42)

Anne Huber 1 , Christine Dijkstra 1 , Matthias Ernst 1 , Moritz Eissmann 1
  1. Olivia Newton-John Cancer Research Institute, Melbourne/Yallambie, VICTORIA, Australia

Background

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. One proposed mechanism of immune escape is silencing tumour‑antigen expression, and thereby avoiding immune recognition. DNA methyltransferases (DNMTs) are the enzymes responsible for epigenetic silencing of gene expression and are often overexpressed in solid tumours. Epigenetic drugs inhibiting these DNMTs have shown anti‑tumour effects in combination with immune checkpoint inhibitors. 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.

 Methods

This project utilises various mouse models of GC. We established a Dnmt3a‑overexpressing inflammation‑driven GC mouse model (gp130FF, A33Dnmt3a). In a second mouse model, mutant Kras, Pi3kca and Tp53 expression results in highly advanced invasive gastric carcinoma formation (KPT model). We successfully established GC organoids of one of these triple mutant tumours, which can be injected subcutaneously into wild type mice and result in allograft tumour formation.

 Results

Gastric adenomas of our gp130FF, A33Dnmt3a mouse model have a 10-fold elevated Dnmt3a expression. Importantly, tumour‑specific Dnmt3a overexpression significantly increased gastric tumour burden. In the KPT model, we have identified DNMT3A as being highly expressed in the invasive front of tumours, their liver metastases as well as in the allograft tumours established by the KPT organoids. In this model of advanced GC, treatment with the DNMT inhibitor decitabine significantly decreased tumour growth and we are currently investigating the efficacy of decitabine in combination with anti‑PD‑1 immunotherapy.

 Conclusion

Taken together, we provide evidence for a driver function of Dnmt3a in gastric tumorigenesis and gastric tumour growth. In addition, our findings encourage further studies to investigate the potential of DNMT inhibitors for the treatment of GC.