GRANTEE: Cosimo Commisso, PhD
Sanford Burnham Prebys Medical Discovery Institute
Research Project: Targeting macropinocytosis via Na+/H+ exchanger inhibition in PDAC
Award: 2015 Skip Viragh – Pancreatic Cancer Action Network – AACR Career Development Award
Award Period: July 1, 2015 – June 30, 2017
Dr. Cosimo Commisso earned his PhD from the University of Toronto where his work centered on endocytosis in the Notch signaling pathway. Dr. Commisso’s research interests became focused on endocytosis and pancreatic cancer while a postdoctoral fellow at New York University School of Medicine in the lab of Dafna Bar-Sagi, PhD. During that time, Dr. Commisso was awarded a Fellowship from the Pancreatic Cancer Action Network, funded in memory of Samuel Stroum. As a postdoctoral fellow, Dr. Commisso led a collaborative study that demonstrated for the first time that Ras-mutated tumors augment their metabolism by boosting macropinocytosis-dependent protein catabolism. Importantly, in Ras-driven tumors, the blockade of macropinocytosis resulted in reduced tumor growth; therefore macropinocytosis and, by extension, its associated regulators, represent novel targets for the development of anti-cancer therapies. Dr. Commisso is currently an assistant professor at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Calif., where his research program is built around identifying novel translational targets within the Ras-stimulated macropinocytosis pathway.
The most commonly mutated protein in pancreatic cancer, KRAS, has multiple functions within the cancer cells. One role of KRAS is to drive a process called macropinocytosis, whereby pancreatic cancer cells take up fluid from outside the cell as a way to bring nutrients into the cell. The process of macropinocytosis is dependent on the activity of a type of protein called a sodium/hydrogen exchanger (Na+/H+ exchanger or NHE). NHE activity can be blocked by a drug called 5-(N-ethyl-N-isopropyl) amiloride (EIPA). Preliminary experiments have suggested that EIPA can inhibit the growth of pancreatic tumors implanted into mice.
Dr. Commisso and his research team will explore the role of NHE in pancreatic tumor growth and explore the potential of EIPA as a therapeutic agent to treat pancreatic cancer. Also, novel inhibitors of NHE will be investigated to see if they can block macropinocytosis and thus slow or stop the growth of pancreatic cancer cells, alone or in combination with chemotherapy. In the future, Dr. Commisso’s work could lead to the design of NHE-specific drugs that could improve the clinical outcomes for patients suffering from pancreatic cancer.