Adding immunotherapy to new KRAS inhibitors boosted responses in preclinical models, setting the stage for future trials of the combination strategy.
Adding immunotherapy to new KRAS inhibitors boosted responses in preclinical models, setting the stage for future trials of the combination strategy.kept pancreatic cancer at bay in preclinical models for significantly longer than the same targeted therapy by itself, according to researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine's Abramson Cancer Center.
The results, published inPatients with pancreatic cancer have an overall poor prognosis: in most patients, the disease has already spread at the time of diagnosis, resulting in limited treatment options. Nearly 90 percent of pancreatic cancers are driven by-mutant cancers can quickly evolve to resist therapies targeted at one specific form of the gene mutation.inhibition for pancreatic cancer, which remains one of the deadliest and most difficult forms of cancer to treat," said co-corresponding senior author Ben Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research and director of the Penn Pancreatic Cancer Research Center."While the first wave ofinhibition tools may have an immune stimulatory effect, making them ideal to pair with immunotherapy for longer and better treatment response." Previous research led by Stanger and Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center, who is also co-corresponding author on this study, showed that a small molecule inhibitor specifically targetingthe form of the mutation more commonly found in pancreatic cancer, stimulated the immune system while shrinking tumors or stopping cancer growth in preclinical mouse models of pancreatic cancer.In this study, the researchers used RAS multi-selective inhibitors, the investigational agent daraxonrasib and the preclinical tool compound RMC-7977 . These inhibitors use a different mechanism of action than most othermutation emerges, the treatment may not necessarily stop working," Vonderheide explained. The research team found that not only was RAS multi-selective inhibition effective in preclinical pancreatic cancer models, but it was even more effective when combined with immunotherapy. Using the combination approach, all mouse models had tumor shrinkage and half had a complete response, meaning the tumor was eliminated. The research team used a Penn-developed immunocompetent model considered the gold standard worldwide for assessing potential therapies for pancreatic ductal adenocarcinoma. This model allows the tumor to spontaneously evolve after implantation, making it possible to discern the drug's impact on the surrounding tumor microenvironment. The research team found that RAS multi-selective inhibition reshaped the tumor microenvironment by bringing in more T cells and other immune cells, making the tumor particularly receptive to immunotherapy.Daraxonrasib is already being tested in clinical trials across the United States. A clinical trial testing RAS inhibitors with other anticancer agents in certain patients with gastrointestinal solid tumors is now open at several sites across the country, including at Penn Medicine. Click here for more information about the study.therapy for pancreatic cancer," Vonderheide said."After decades of limited progress, it's encouraging to see new treatment approaches making their way into the clinic for patients." The study was supported by Revolution Medicines, the National Institutes of Health the Department of Defense , the Molecular Pathology and Imaging Core, A Love for Life, the Basser Center for BRCA, and the Penn Pancreatic Cancer Research Center. Information for patients interested in joining a clinical trial: visit Penn Medicine's Abramson Cancer Center Clinical Trial Information Service online or call 1-855-216-0098 to speak to a clinical trial navigator.Margo I. Orlen, William P. Vostrejs, Rina Sor, Jayne C. McDevitt, Samantha B. Kemp, Il-Kyu Kim, Adam B. Kramer, Nataliya Tovbis Shifrin, Nune Markosyan, Cynthia Clendenin, Mallika Singh, Elsa Quintana, Marie Menard, Robert H. Vonderheide, Ben Z. Stanger.Researchers have uncovered a functional role for KRAS mutations in pancreatic cancer and rapidly translated these findings into a novel therapeutic approach combining a KRAS G12D inhibitor with ... Researchers have discovered a novel immunotherapy combination, targeting checkpoints in both T cells and myeloid suppressor cells, that successfully reprogrammed the tumor immune microenvironment ... A team of researchers has developed an immunotherapy strategy that can eliminate pancreatic tumors in mice. The new therapy, a combination of three drugs that boost the body's immune defenses ... In mice treated with cancer immunotherapy, shining a cosmetic laser on a tumor boosted the therapy's effectiveness. The strategy stimulated the immune system to attack nonmutated proteins on the ...
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