GRANTEE: Marco Biancucci, PhD
Northwestern University – Chicago Campus
Research Project: Ras Inhibition by a Novel Bacterial Protease
Award: 2016 Samuel Stroum – Pancreatic Cancer Action Network – NCI Frederick National Laboratory for Cancer Research KRAS Fellowship
Award Period: April 1, 2016 – March 31, 2017
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. He spent part of his graduate program at Novartis Vaccine and Diagnostics, also in Siena, under the supervision of Dr. Rino Rappuoli. As a graduate student, Dr. Biancucci worked on developing new vaccines for different types of bacteria that make people sick. In his current position, under the mentorship of Dr. Karla Satchell, Dr. Biancucci is studying a bacterial protease that cleaves the KRAS protein, which is mutated in almost all human pancreatic cancer cases.
Dr. Biancucci’s project focuses on the effects and mechanism of a bacterial protease called RRSP. A protease is a type of protein that functions by cleaving, or cutting, other proteins. Protein cleavage causes structural and functional changes to the target protein. RRSP was found to cleave RAS proteins, including KRAS. KRAS is mutated in 95 percent of human pancreatic cancer cases, and its activity is known to directly contribute to the initiation and progression of the disease. RRSP is naturally produced by the bacterium Vibrio vulnificus, and it cleaves RAS in order to inactivate the innate immune response of the host cells, thus preventing their ability to fight off the bacterial infection. The research team hopes to exploit this alteration by RRSP cleavage as a way to alter KRAS activity in pancreatic cancer cells.
Dr. Biancucci proposes to understand how cleavage by RRSP changes the three-dimensional structures of normal and mutant KRAS. These structural changes are theorized to change the activity of both normal and mutant KRAS, possibly in different ways, which will in turn alter the protein signaling cascade stimulated by KRAS. By looking at the structure of both the cleaved normal and mutant KRAS proteins, Dr. Biancucci hopes to gain insight on how the cleavage might affect the function of mutant KRAS in pancreatic cancer cells. He also hypothesizes that a better understanding of the mechanism by which the RRSP enzyme cleaves KRAS could be utilized to design future therapeutics. Dr. Biancucci will use a combination of structural biology and biochemistry techniques that are in line with the biochemistry project area that is part of the National Cancer Institute’s RAS Initiative, where investigators are also utilizing structural and biochemical approaches to learn about the RAS family of proteins.