The survival rate for patients diagnosed with stromal sarcoma of the uterus (ESS)—a rare cancer that forms in the connective tissues of the uterus—is extremely low. In a new study, Yale School of Medicine (YSM) researchers uncovered potential treatment strategies by establishing a more detailed understanding of the aggressive tumors at the molecular level.
Their findings were reported in Proceedings of the National Academy of Sciences.
For the study, Yale Cancer Center (YCC) researchers at YSM analyzed the genetic landscape of ESS tumors from 80 individuals. Using cutting-edge techniques, they sequenced all of the genes from each of the tumors and identified mutations that were critical for the tumors to grow and evade cancer treatments.
The study revealed atypical genes and cell signaling pathways that might be targeted with precision medicine approaches, and the findings suggest some of these highly aggressive tumors might respond to existing targeted therapies.
The research was an international collaboration among research groups in Italy, Norway, South Korea, and the United States.
“Our findings have important implications for a better understanding of the genetic fingerprint of ESS as well as the development of novel therapies against these biologically aggressive uterine sarcomas,” says senior author Alessandro Santin, MD, co-chief of the division of gynecologic oncology at YCC and a professor of obstetrics, gynecology, and reproductive sciences at YSM. “Our genetic data validated preclinically in animal models suggest that FDA-approved regimens based on the use of MEK and FAK inhibitors, which block signaling pathways that are key for cancer cell growth, may represent a potentially effective treatment for a subset of these patients.”
The researchers sequenced both low-grade and high-grade ESS tumors; the former are typically slower to grow while the latter have very abnormal cells and tend to grow quickly. The findings support for the first time the interpretation that these tumors arise through fundamentally different biological pathways and are not sequential points along a single progression trajectory.
“Our findings favor a model in which high-grade ESS does not occur from low-grade ESS but instead represents a genetically and clinically distinct disease entity,” says Tobias Hartwich, PhD, first author of the study and associate research scientist in Santin’s laboratory.
The study team also created a human tumor model by introducing ESS tumor tissue into immunodeficient mice, an approach that’s key to testing novel drugs against the tumors, says study co-author Joseph Schlessinger, PhD, William H. Prusoff Professor of Pharmacology at YSM. The model was used to test and validate novel targeted treatment options against ESS, and the findings could help predict clinical responses and inform new treatments tailored to individual patients.