Dana-Farber Cancer Institute has launched the Center for RAS Therapeutics, aiming to develop drug therapies for RAS-driven cancers. RAS gene mutations are found in 20% of all cancers and are associated with lower survival rates compared to those without RAS gene mutations.
The new center will be led by Alice Shaw, MD, PhD, thoracic medical oncologist and chief of strategic partnerships at Dana-Farber, and Andrew Aguirre, MD, PhD, gastrointestinal medical oncologist and physician-scientist at both Dana-Farber and Cambridge, Mass.-based Broad Institute of Harvard and MIT.
The center will accelerate drug development to improve outcomes as well as support preclinical studies and clinical trials of newly developed RAS inhibitor therapies, according to the release.
Focus on Overcoming Drug Resistance
One of the key priorities of the center is to provide access to new therapies for RAS-driven cancers through clinical trial participation. Dana-Farber boasts one of the largest portfolios of clinical trials investigating novel therapies for cancer patients, including therapies designed specifically for patients with KRAS-mutant cancers. The new RAS Center will work closely with investigators and with industry partners to identify the most promising clinical trials to open at Dana-Farber, based on mechanism of action, preclinical data, and the evolving treatment landscape.
"While RAS-targeting therapies hold tremendous promise, treatment resistance remains a significant problem that will require innovative combination therapy approaches," said Dr. Aguirre in the release. "The landscape of new RAS inhibitors is highly complex and centralized expertise is necessary to determine the right drug or combination of drugs for every patient. We will work closely with other academic and industry partners with the goal to improve our understanding of treatment resistance across tumor types, to discover new vulnerabilities in RAS-driven cancers, and to conduct the most efficient clinical trials of new therapies."
Clinical Trials and Research
Dana-Farber investigators have been actively driving the development of new KRAS inhibitors, including the KRASG12C inhibitor adagrasib which is now FDA approved for patients with previously treated, KRASG12C-mutant lung cancer and KRASG12C-mutant colorectal cancer. There are also newer promising therapies like RMC-6236, a multi-selective RAS inhibitor which is being evaluated in a randomized phase 3 trial for patients with previously treated advanced pancreatic cancer.
While early therapeutic strategies targeting KRAS have shown promising results, some patients do not respond, and some patients who do respond eventually develop drug resistance leading to worsening disease. Dana-Farber investigators have played a major role in not only developing new targeted therapies but also discovering mechanisms of resistance to these therapies. Understanding why cancers become resistant is critical to developing new and more effective therapeutic strategies in the clinic.
Investigators in the RAS Center have a special interest in resistance to RAS-targeted therapies. Our investigators published one of the first reports on resistance to KRASG12C inhibitors in the New England Journal of Medicine. In this study, resistant cancers from patients with KRASG12C-mutant lung and colorectal cancers were comprehensively profiled at the genomic level to discover multiple different mechanisms of resistance to adagrasib. We also recently reported the discovery of mechanisms of resistance to KRASG12C and KRASG12D inhibitors in clinical samples and preclinical models of pancreatic cancers. These and other studies have revealed fundamental insights into the biology of resistance and provided the scientific basis for developing new combinatorial strategies designed to overcome resistance.
At present, there are no effective therapeutic strategies that can overcome resistance in KRAS-mutant cancers. Based on the latest research, we are pursuing many different combination strategies in the clinic, including combinations with cytotoxic chemotherapy, immunotherapy such as PD-1/PD-L1 inhibitors, and other targeted therapies such as Ras/MAPK pathway inhibitors and PRMT5 inhibitors. Our clinical trials may be industry sponsored and involve close collaboration with both the drug manufacturer and other academic sites. Other trials and studies may be investigator-initiated based on preclinical data developed at Dana-Farber using various cancer models such as patient-derived xenograft models, organoid models, or genetically engineered mouse models.
Patients who are eligible for these clinical trials and research studies on resistance include those with RAS-mutant cancers who have previously received a RAS-targeted therapy. In some cases, these trials and studies may also include patients who have never received a RAS-targeted therapy to investigate whether a new approach may be able to prevent the development of resistance.
