GRANTEE: Nipun Merchant, MD
University of Miami
Co-Principal Investigator: Michael VanSaun, PhD
Research Project: Targeting downstream effectors of KRAS via MEK and CDK-4 inhibition in PDAC
Award: 2015 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2015 – June 30, 2017
Dr. Merchant is currently the Alan S. Livingstone Endowed Professor of Surgery at the University of Miami Medical Center where he is the vice chair of surgical oncology services and the chief of the division of surgical oncology in the department of surgery. He also serves as the chief surgical officer and is the director of surgical oncology research of the Sylvester Comprehensive Cancer Center. He is a recognized leader in the clinical management of hepato-pancreatico-biliary and neuroendocrine malignancies. Dr. Merchant also has an active basic science and translational research laboratory. Dr. Merchant joined the Pancreatic Cancer Action Network’s Scientific and Medical Advisory Board in 2015.
Dr. VanSaun received his PhD in anatomy and cell biology from the University of Kansas Medical Center in 2003. He then joined Vanderbilt University in 2004 as a research fellow, first completing his postdoctoral training in the department of cancer biology, and then advancing to a research instructor in the departments of surgery and cancer biology in 2009. In 2010, Dr. VanSaun received a Career Development Award from the Pancreatic Cancer Action Network. Dr. VanSaun was promoted in 2015 to a research assistant professor in the department of surgery at the University of Miami. He hopes to identify novel molecular mediators of pancreatic cancer progression and determine their potential for prevention and/or therapeutics.
One of the major hurdles to effectively treating pancreatic cancer is the high number and complexity of genetic changes that contribute to disease initiation and progression. While KRAS is the most frequently mutated protein in pancreatic cancer, there are many other mutations in proteins whose functions are interconnected and overlap with KRAS and each other. To date, efforts to directly target the activity of mutant KRAS have been unsuccessful. One of the key proteins activated by mutant KRAS is called MEK, and there are drugs being tested to block the activity of MEK. However, pancreatic cancer cells devise mechanisms to become resistant to MEK inhibition, including via activation of proteins called CDK4 and CDK6.
Drs. Merchant and VanSaun and their research teams propose to combine blockade of MEK and CDK4/6 activity in pancreatic cancer cells as a treatment strategy. Encouragingly, preliminary data show that combined inhibition of MEK and CDK4/6 increases the survival of a highly aggressive pancreatic cancer mouse model by 400 percent. For their proposed project, the researchers plan to further examine the timing, dose, potency and potential side effects of this treatment in mice. In addition, they will assess whether a tumor’s genetic profile may predict that patient’s likelihood of response. Successful completion of these aims will optimize this treatment regimen and identify a molecular tumor profile in patients that will maximally benefit from this therapy.