2020 Grantee: Mustafa Raoof, MD, FACS
Beckman Research Institute of the City of Hope
Research Project: Targeting Transcription-Replication Conflicts in Pancreatic Cancer
Award: 2020 Pancreatic Cancer Action Network Career Development Award in memory of Skip Viragh
Award Period: Jan. 1, 2021 – Dec. 31, 2022
Dr. Raoof is a surgical oncologist and an assistant professor of surgery at City of Hope, a comprehensive cancer center. He is focused on the surgical treatment of gastrointestinal cancers and pancreatic cancer in particular. After graduating from Aga Khan University medical school in Pakistan, Dr. Raoof completed his surgical internship at Yale, residency at University of Arizona and surgical oncology training at City of Hope. During his training, Dr. Raoof completed postdoctoral fellowships at Beth Israel Deaconess Medical Center (Harvard Medical School) and MD Anderson in immunology and cancer biology, respectively.
Besides clinical practice, Dr. Raoof conducts laboratory research focusing on DNA damage avoidance and repair mechanisms in pancreatic cancer. By identifying and characterizing these processes in pancreatic cancer, he is working to develop better targets for future therapies.
He is the author of dozens of peer-reviewed papers that have been published in leading scientific journals, including Nature, Journal of the National Cancer Institute and Biomaterials. Dr. Raoof is the recipient of several honors and awards, most notably, the Conquer Cancer Foundation Merit Award from the American Society of Clinical Oncology, the Society of Thermal Medicine’s Biology Informa-Yamamoto Young Investigator Award, the American College of Surgeons Faculty Research Fellowship and the National Comprehensive Cancer Network Young Investigator Award.
Pancreatic cancer growth is driven by a mutation in the KRAS gene in 95% of tumors. This mutation results in an activated version of the KRAS protein that signals the cancer cell to divide constantly. Cell division requires duplication of DNA (replication). In addition, activated KRAS places significant demands on the cell to make abundant proteins for cell growth.
The first step in the process of making proteins is to copy the message stored in the DNA to messenger RNA (the process is called transcription). Given the increased rates of replication and transcription, the molecular machineries that perform these functions frequently come into conflict. Unresolved conflict can cause transcription and replication machineries to collide, resulting in lethal DNA damage.
Contrary to normal cells, pancreatic cancer cells depend on powerful mechanisms to avoid such collisions in order to survive. Dr. Raoof’s laboratory is focused on targeting transcription-replication conflicts by: 1) inhibiting conflict resolution pathways to promote more collisions; 2) turning collisions into lethal DNA damage.
Dr. Raoof has already identified a novel compound that causes lethal DNA damage and transcription shutdown at sites of collisions. The studies proposed in this project will investigate targeting conflict resolution pathways to enhance transcription-replication collisions and lethal DNA damage. Specifically, Dr. Raoof will focus on a key protein called RECQ5 that is critical in the conflict resolution pathway. The approach proposed here could lead to a more effective treatment for individuals with KRAS-driven pancreatic cancers.