Targeting BRCAness in Gastric Cancer

This application aims at improving outcomes for patients with stomach cancer, a 2015 PRCRP Congressionally Directed Topic Area. Germline as well as somatic mutations in genes involved in DNA repair by homologous recombination (HR) are common in stomach cancer. For example, BRCA1/2 mutations are found in 15 percent of gastric cancers and are associated with poor survival. As partnering PI Dr. Ashworth has demonstrated, the DNA repair protein PARP compensates for loss or BRCA protein in BRCA1/2 mutant cells rendering such cells exquisitely sensitive to inhibition of PARP. Furthermore, tumors characterized by genomic instability (resulting in extensive loss of heterozygosity) and susceptibility to PARP inhibitors or platinum agents in the absence of BRCA1/2 mutations have been identified, a phenomenon known as "BRCAness". We expect that 25 percent of advanced gastric cancers harbor mutations conferring "BRCAness". Published data suggests that the PI3 kinase pathway regulates HR repair and our own data suggest that MEK inhibitors synergize with PARP inhibitors. With this application, we aim at identifying additional mechanisms regulating HR repair that could be exploited therapeutically. In addition, due to the high mutational burden associated with BRCAness, it is to be expected that BRCA1/2 mutations or BRCAness result in susceptibility to PARP inhibitors. Studies proposed here will be carried out in context with clinical trial designed by us (PI: Korn) to test the PARP inhibitor talazoparib in combination with chemotherapy in patients with gastroesophageal whose tumors harbor BRCA1/2 mutations or mutations conferring BRCAness. Enrollment will begin during the first quarter of 2016. Hypothesis. We hypothesize that gastric cancers displaying BRCAness are susceptible to PARP inhibition.