2017 GRANTEE: Marco Biancucci, PhD
Northwestern University – Chicago Campus
Research Project: Targeting KRAS Switch I with Highly Specific Bacterial Endopeptidase
Award: 2017 Pancreatic Cancer Action Network – NCI, Frederick National Laboratory for Cancer Research KRAS Fellowship
Award Period: July 1, 2017 – June 30, 2019
Dr. Biancucci is a postdoctoral research fellow in the department of microbiology-immunology at Northwestern University – Chicago Campus. Dr. Biancucci received his MS in biotechnology and his PhD in chemical science from the University of Siena, Italy. Dr. Biancucci has been awarded the 2016 Samuel Stroum – Pancreatic Cancer Action Network – NCI Frederick National Laboratory for Cancer Research KRAS Fellowship. In his current position, under the mentorship of Dr. Karla Satchell and in collaboration with scientists of the National Cancer Institute (NCI) RAS Initiative, Dr. Biancucci is studying a bacterial protease (RRSP) that cleaves the KRAS protein, which is mutated in almost all human pancreatic cancer cases. During the last year, Dr. Biancucci defined the specificity and the cleavage mechanism of RRSP.
One of the ways that bacteria can survive within a hostile host environment is to cleave, or cut apart, certain proteins in order to block an immune response. Dr. Biancucci and his colleagues have discovered that a bacterial toxin known as RRSP cleaves a certain type of protein called small GTPases – and the most commonly mutated protein in pancreatic cancer, KRAS, is a small GTPase.
KRAS is mutated in upwards of 90 percent of pancreatic cancer cases, and its activity has been shown to be a driving factor for the initiation and progression of the disease. Therefore, decades of research have focused on devising a strategy to directly or indirectly block mutant KRAS activity, but these efforts have not been successful to date.
For his project, Dr. Biancucci aims to determine whether RRSP’s ability to cleave mutant KRAS can be exploited for drug development. First, he will identify which amino acids, or protein building blocks, within KRAS physically interact with RRSP. Next, the research team will evaluate the activity of RRSP in pancreatic cells that express mutant KRAS that are grown in a dish. Finally, the researchers will determine how cleavage by RRSP affects the KRAS protein’s positioning on the membrane surrounding pancreatic cancer cells.
The planned research promises to reveal new structure and function information of KRAS inhibition by RRSP. Further, knowledge of the mechanism of RRSP processing and inhibition of KRAS could facilitate development of RRSP or RRSP mimics as novel therapeutics for pancreatic cancer patients.