2019 Grantee: Andrew Lowy, MD, FACS
University of California, San Diego
Research Project: MICAL2: A Novel Super-Enhancer Associated Target in Pancreatic Cancer
Award: 2019 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2019 – June 30, 2021
Andrew M. Lowy, MD, FACS, is professor of surgery, chief of the division of surgical oncology and leader of the Gastrointestinal Oncology Program at the Moores UCSD Cancer Center. Dr. Lowy did his residency training at Cornell/New York Hospital and his surgical oncology training at the MD Anderson Cancer Center.
Dr. Lowy ‘s clinical practice and research focus on pancreatic cancer. He runs a basic research laboratory that has been continuously funded by the National Institutes of Health (NIH) since 1999 and is also currently funded by Stand Up To Cancer. His laboratory co-developed the first genetically engineered mouse model of pancreatic cancer and currently focuses on the identification and testing of novel therapeutic targets in pancreatic cancer.
Dr. Lowy was recently named chair of PanCAN’s Scientific & Medical Advisory Board and serves on the board of the National Pancreas Foundation. He served as co-chair for the National Cancer Institute’s Pancreatic Cancer Task Force from 2007-2016 and has served as chair since 2016.
There is an urgent need to develop more effective therapies for pancreatic cancer, and it has become clear that this requires an understanding of the signals that drive the disease’s growth and metastasis that go beyond a characterization of genetic mutations.
Super-enhancers are short fragments of DNA that function to regulate gene expression. Super-enhancer-associated genes are known to be key determinants of cell identity. Dr. Lowy and his colleagues hypothesized that abnormal super-enhancer activation is critical to the “pancreatic cancer state,” and that by identifying super-enhancer-associated genes, they could identify new targets for effective pancreatic cancer treatment.
Thus, the research team mapped super-enhancers in normal and pancreatic cancer tissue from primary patient samples. Super-enhancer profiling of pancreatic cancer tissue revealed a distinctive landscape compared to that of the normal pancreas. Amongst the most highly differentially expressed genes was MICAL2, which encodes a protein that regulates levels of nuclear actin, the most abundant cytoskeletal protein (structural protein that gives cells their shape). Through control of nuclear actin levels, MICAL2 controls the levels of numerous genes important for cancer growth and metastasis.
Dr. Lowy’s preliminary work has demonstrated that silencing (turning off) MICAL2 leads to reduced pancreatic cancer growth and metastasis in cells grown in a dish and in mouse models, respectively. This suggests that drugs that can inhibit MICAL2 function could provide an exciting new avenue for pancreatic cancer treatment. In this proposal, the investigators will study 1) the molecular mechanisms by which MICAL2 promotes pancreatic tumor growth and metastasis and 2) utilize various pancreatic cancer laboratory models to determine the therapeutic benefit of targeting MICAL2 in pancreatic cancer.