Their study, to be published May 6th in Science Signaling, demonstrates in animal models and in human cancer cells that while suppressing Yap-associated protein (Yap) did not prevent pancreatic cancer from first developing, it stopped any further growth.
“We believe this is the true Achilles heel of pancreatic cancer, because knocking out Yap crushes this really aggressive cancer. This appears to be the critical switch that promotes cancer growth and progression,” says the study’s senior investigator, Chunling Yi, PhD, an assistant professor of oncology at Georgetown Lombardi.
Yi added that because Yap is over-expressed in other cancers, such as lung, liver and stomach tumors, researchers are already working on small molecule drugs that will inhibit activity of the protein and its partnering molecules.
The study was conducted in mouse models of pancreatic ductal adenocarcinoma (PDAC), which accounts for all but five percent of human pancreatic cancers. These mice have a mutation in the KRAS gene, as well as a mutation in their p53 gene. “More than 95 percent of pancreatic cancer patients have a KRAS mutation and about 75 percent have a mutation in p53, so these mice provide a natural model of the human disease,” she says.
Because it has been very difficult to devise drugs that target either KRAS or p53, in this study the researchers looked for other potential druggable targets involved in uncontrolled growth of pancreatic cancer.
They found that Yap was over-expressed in both mouse models and human samples of PDAC, and they discovered that the KRAS mutation found in most pancreatic cancer activates Yap. “The KRAS mutation uses Yap to make cancer cells grow, so shutting down Yap defuses the mutated gene’s activity,” Yi says.
Yap also shuts down activity of the p53 oncogene, though the link between p53 and Yap is not yet known.
“KRAS and p53 are two of the most mutated genes in human cancers, so our hope is that a drug that inhibits Yap will work in pancreatic cancer patients — who have both mutations — and in other cancers with one or both mutations,” Yi says.
Georgetown Lombardi co-authors include oncologist and professor Anton Wellstein, MD, PhD, and pediatric oncologist and professor Jeffrey Toretsky, MD.
The authors report having no personal financial interests related to the study.
External funding for this research provided by the National Cancer Institute (CA71508), a Burroughs Wellcome Clinical Scientist Award in Translational Research and the National Institutes of Health (R01CA133662 and R01CA138212).
About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute (grant #P30 CA051008), and the only one in the Washington, DC area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.