NEW YORK – Mount Sinai said Wednesday that it has been awarded a three-year, $500,000 grant from Stand Up To Cancer (SU2C) to investigate treatments for lung tumors bearing KRAS mutations.
The grant will enable Mount Sinai researchers to partner with New York University researcher Kwok-Kin Won to study therapeutic combinations for KRAS-mutant non-small cell lung cancer using JZP815, a pan-RAF inhibitor developed by Redx and sold to Jazz Pharmaceuticals in 2019. Jazz partnered with SU2C in 2021 to develop treatments for children with solid cancers and advance therapeutics targeted to RAF- and RAS-mutated solid cancers.
JZP815 targets the MAPK pathway, which is linked to a higher risk of cancer-related deaths among patients with KRAS-mutant lung cancers. In addition to inhibiting RAF signaling, it also prevents paradoxical pathway activation caused by selective BRAF inhibition.
In the project, researchers will employ genetically engineered KRAS-mutant, mouse-derived cell lines to identify tumor vulnerabilities related to treatment with JZP815 that can be exploited by combining it with other therapeutic agents.
"Typically, when patients with advanced NSCLC with a KRAS mutation receive therapeutics, there is a period of regression and then the cancer recurs, which is the paradigm in lung cancer more generally," said Fred Hirsch, a professor of hematology and medical oncology at Mount Sinai's Icahn School of Medicine. Ideally, through their research into combination treatments, patients will have more enduring benefits.
Resulting therapeutic combinations will be screened using patient-derived organoids and mouse models to validate the in vitro results and to develop biomarkers that can be used to identify patients most likely to benefit from the combination therapy.
KRAS mutations occur in approximately 30 percent of all NSCLC cases and are associated with a higher risk of death compared to tumors without these aberrations.
Amgen's KRAS inhibitor Lumakras (sotorasib) is currently available for metastatic NSCLC patients with KRAS G12C mutations. The company and other competitors are also exploring combination treatment approaches with their KRAS inhibitors.