Using an innovative approach to identify a cancer’s genetic vulnerabilities by more swiftly analyzing human tumors transplanted into mice, researchers have identified a new potential target for pancreatic cancer treatment, published online in Cell Reports.
The team, led by scientists at The University of Texas MD Anderson Cancer Center, found the gene WDR5 protects pancreatic tumors from DNA damage, working with the previously known cancer-promoting gene called Myc to help tumors thrive.
“The WDR5-Myc connection is essential for the pancreatic cancer cells to proliferate,” said study co-first author Alessandro Carugo, Ph.D., institute research scientist at MD Anderson’s Institute for Applied Cancer Science (IACS).
Their discovery is a demonstration project for technology currently established at MD Anderson’s Center for Co-Clinical Trials to evaluate gene function in a more realistic, living model of human cancers.
“This new technology allows us to more rapidly identify genetic drivers that maintain a tumor and thus potentially find new ways to treat it,” said Giulio Draetta, M.D., Ph.D., director of IACS and professor of Genomic Medicine and Molecular and Cellular Oncology.
Functional genetic screening can be conducted in cancer cell lines in the lab, Carugo notes, but cell lines do not represent the challenging genomic complexity of an actual tumor.
Researchers have been taking bits of tumor surgically removed from patients, transplanting them in mice, and using them to discover new avenues for treating the comparable human tumors.
These human tumors in mice, called patient-derived xenografts (PDX), have not been subject to large-scale functional genetic screening like cell lines are, Carugo said. “What’s really different here is that we are applying functional screening on patient-derived xenografts.”
PILOT provides faster screening
The team’s method is called Patient-Based in Vivo Lethality to Optimize Treatment (PILOT). It allows for the analysis of hundreds of tumor genes using only a few mice.
PILOT technology is being applied in MD Anderson’s Moon Shots Program, which is designed to reduce cancer deaths by more rapidly developing new treatments, early detection methods and prevention programs based on scientific discoveries. The technology is being used to analyze PDXs in pancreatic, lung, colorectal and head and neck cancers. CCCT and IACS are platforms for the Moon Shots Program.
Typically, researchers take a PDX, expand the tissue, transplant it in 30 or more mice, and then test one drug compound against the tumor in each mouse.
“With PILOT, instead of expanding the sample to challenge it with different drugs one at a time in many mice, we apply many more tests to a few mice to identify genomic drivers,” Carugo said.