2018 Grantee: Andrew Aguirre, MD, PhD
Dana-Farber Cancer Institute
Research Project: Functional Genetic Discovery of Novel Targets in Pancreatic Cancer
Award: 2018 Skip Viragh Pancreatic Cancer Action Network Catalyst Grant
Award Period: July 1, 2018 – June 30, 2021
Dr. Aguirre is a physician-scientist and medical oncologist at Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT. Dr. Aguirre was an undergraduate at the University of Michigan and then earned MD and PhD degrees from Harvard Medical School. His graduate work focused on developing mouse models of pancreatic cancer in the laboratory of Dr. Ronald DePinho. He completed a residency and chief residency in internal medicine at the Massachusetts General Hospital, and then trained in medical oncology at Dana-Farber Cancer Institute. Dr. Aguirre performed his postdoctoral studies with Dr. William Hahn and Dr. Brian Wolpin, where he focused on 1) identifying new therapeutic targets (unique aspects of cancer cells that can be targeted by drugs) in pancreatic cancer and 2) developing a personalized approach to pancreatic cancer treatment based on studies of patient-specific tumor models. During that time, Dr. Aguirre was the recipient of a Fellowship Award from the Pancreatic Cancer Action Network, funded in memory of Samuel Stroum.
Dr. Aguirre practices medical oncology and leads an independent pancreatic cancer research laboratory at Dana-Farber Cancer Institute. He is devoted to improving treatment options for pancreatic cancer patients.
The KRAS oncogene is mutated in most pancreatic cancers and is the major genetic driver of this disease. Unfortunately, attempts to develop drugs that target mutant RAS proteins have been unsuccessful. When KRAS is activated, it turns “on” the activity of other proteins known as the MAP-kinase pathway, which ultimately results in uncontrolled cellular growth, survival and other common features of cancer cells.
While some treatments, known as inhibitors, can block the activity of these MAP-kinase proteins, they have been ineffective in pancreatic cancer patients. This is in part due to a complex set of compensatory signaling pathways that become active in the presence of these MAP-kinase inhibitors and promote the survival of pancreatic cancer cells. Many of these survival pathways are intrinsic to the cancer cells, whereas others may come from the stroma, a dense and complex network of tissue types that surrounds and infiltrates pancreatic tumors.
Identifying these survival signals may enable development of new treatment strategies that can be combined with RAS pathway inhibition. Through this project, Dr. Aguirre and his colleagues will leverage large-scale genetic screening data performed in many different pancreatic cancer cell lines that have identified new selective vulnerabilities, or synthetic lethal targets, in combination with MAP-kinase inhibition.
Specifically, the research team seeks to confirm two potential therapeutic targets that, when blocked, appear to cause cell death in combination with MAP-kinase inhibitors. Finally, they propose to utilize an innovative approach to identify additional genes whose activity may compensate for weakened MAP-kinase or KRAS-generated signaling. Through these studies, Dr. Aguirre hopes to develop new combination therapy approaches for pancreatic cancer patients.