Novel Theraputic Approaches for DDR Mutant Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal human malignancy, typically diagnosed at an advanced stage and is known to be largely unresponsive to chemotherapy and ionizing radiation. With the increased use of genomic profiling, distinct subtypes of pancreatic cancer have been identified.
PDA patients that exhibit DNA damage repair deficiency (DDR), a full 20-25% of PDA patients, demonstrate a more favorable response to DNA damaging agents. This has indeed been shown to be the case with BRCA1 and BRCA2 mutant PDA, which display outlier responses to platinum agents and PARP inhibitors, resulting in the first potential subtype of PDA (beyond the 1% of pancreatic cancers that have mutations in mismatch repair genes and respond more favorably to checkpoint blockade). Mutations commonly associated with DDR are in the genes BRCA1, BRCA2, and ATM.
ATM, a DDR gene that serves as a master regulator gene of the DDR, is upstream of both BRCA1 and BRCA2 in the DDR. ATM is a serine/threonine protein kinase that regulates cell cycle arrest, DNA repair and apoptosis. ATM germline mutations occur in roughly 4% of PDA patients, and ATM sporadic mutations have been detected in up to 18% of PDAs (Russell et al., 2015), with the majority been missense mutations potentially impairing its kinase activity (Cremona et al., 2014). ATM germline and sporadic mutations are also present in other tumor types, including breast and gastric cancer, however therapeutic strategies to target ATM overall are not well developed.
The goal of this project is to leverage out large portfolio of ATM mutant human PDA cell lines and genetically engineered mouse models to develop a tiered strategy to design new, more effective therapeutics to target ATM-mutant pancreatic tumors. Mouse and patient derived-ATM mutant PDA cell lines will be used to screen standard therapies (e.g. platinums and PARP inhibitors) and perform a large scale, unbiased screen to identify targets/pathways that result in novel synthetic lethality.