Damon Runyon Researchers

Pancreatic cancer may soon become the second leading cause of cancer deaths in the nation. While many cancers have mutations that can be targeted with specific drugs, historically no such targets had been recognized in pancreatic cancer. This changed recently with the discovery that approximately one of every four pancreatic cancers has a defect in the machinery that repairs DNA damage. For example, some have been found to have mutations in the BRCA genes as well as other similar genes involved in repairing double-strand breaks in DNA. Because BRCA-mutant cancers have impaired DNA damage repair, they rely on backup DNA repair systems to survive. Other tumors with BRCA mutations are particularly vulnerable to certain drugs: having such a mutation is an Achilles' heel for the tumor. If the relevant backup systems in these cells can be identified, we can potentially use these dependencies against the tumors. One example of a backup system, the PARP DNA repair system, is currently being targeted in clinical trials in BRCA-mutant pancreatic cancer. Dr. Carnevale aims to uncover multiple vulnerabilities in these cancers that can be targeted with higher efficacy than PARP inhibitors. There may also be candidates for PARP inhibitor combination therapies to more potently eradicate these tumors and/or avoid the development of resistance. She will use a novel screening technology called "CRISPRi" to conduct a genome-wide unbiased exploration for drug targets in pancreatic cancer with DNA-damage repair deficiencies. Any top targets will be prime for translation into an early phase clinical trial for pancreatic cancer patients.