A study found that a new type of experimental treatment for pancreatic cancer has shown remarkable ability to fight tumors in early tests. Revolution Medicines Inc. is developing these oral medications to target active cancer cells. The findings suggest that this new therapy has the potential to provide new treatment options for almost all pancreatic tumors.it is that makes pancreatic cancer so lethal: mutations in a family of genes that code for a protein called RAS. These mutated RAS proteins, including KRAS, NRAS, and HRAS, are responsible for driving around one-third of all human cancers. A team of researchers, led by scientists at Columbia University and Revolution Medicines, has published their findings in Nature, shedding light on potential new pathways for treating this deadly disease. Despite being the third leading cause of cancer-related deaths in the United States, pancreatic cancer has been particularly difficult to treat. The disease claims the lives of approximately 50,000 people each year, and while scientists understand the genetic mutations behind the cancer, finding effective treatments has proven to be a challenge for drug developers and oncologists.causing most instances at the cellular level. Kenneth Olive, PhD, an associate professor of medicine at Columbia University’s Vagelos College of Physicians and Surgeons, stated that the mutated KRAS protein is responsible for driving around 95% of all pancreatic ductal adenocarcinoma cases. He also mentioned that there have been limited direct tools to combat it for the past four decades. Mallika Singh, PhD, who is the vice president for translational research at Revolution Medicines and a co-senior author of the study, informed Olive that the company had made advancements in this area.When Dr. Olive first learned about a new type of inhibitors that could potentially target all RAS mutations, he was skeptical at first. However, he was also curious and decided to collaborate with the team behind the discovery. Preclinical studies were then conducted in Dr. Olive’s lab at Columbia, with Urszula Wasko, a PhD student, leading the research. The initial experiments with RMC-7977 showed promising results, leading Dr. Olive to realize that they were dealing with something completely different. At the same time, Dr. Olive and Revolution Medicines worked on bringing together pancreatic cancer experts from various academic institutions.The University of Pennsylvania, Dana-Farber Cancer Institute, University of North Carolina at Chapel Hill, and Memorial Sloan Kettering are among the institutions involved in this collaborative effort. “Instead of competing with each other, we formed a consortium and agreed to share data in real time. This was a game-changer,” says Olive.
Researchers studying pancreatic cancer have created numerous preclinical models of the disease over the years, each with its own strengths and weaknesses. Instead of choosing just one, the expanded team tested RMC-7977 in all of them. “By bringing together a consortium of scientists to tackle this problem, we were able to investigate active RAS inhibition in every model.”jor class of model for pancreatic cancer, and this inhibitor performed really well in all,” says Olive.
Olive’s lab has a long-standing preference for the preclinical tumor model, which is known for its resistance to treatment. “RMC-7977 as a single agent outperformed the best combination regimen ever reported in the literature in that model system,” he says. Furthermore, it’s the first time he’s witnessed tumors consistently getting smaller in those systems. Similar results were obtained from other models tested by the consortium.
Since RMC-7977 also inhibits wild-type RAS proteins that are essential to the healthThe researchers also carefully studied the normal tissues in the treated animals, in addition to the many normal cells. Their findings revealed that the inhibitor had a unique sensitivity to tumor cells, while its impact on normal cells was minimal. Although the initial responses to the inhibitor in preclinical tumor models were impressive, Olive emphasizes that the tumors were not completely eliminated. “In almost every case, the tumor came back,” he explains. The investigators then identified another oncogene, called MYC, that was altered in most of the resistant tumors in tissue culture. They subsequently developed a combination treatment that proved effective against tumor cells.The study found that the cancer had become resistant to the RAS inhibitor. These findings indicate that a combination approach may be beneficial for future patient treatment. In a field where drug development has often failed, the new results bring hope, according to Olive. He mentioned that in his nearly 20 years of work in pancreatic cancer, he has never seen preclinical results like these. He believes there is a genuine possibility that this approach could change the standard of care for pancreatic cancer patients, but only clinical trials will confirm this. Olive expressed excitement about Columbia’s involvement in the clinical development, as they are just one of many institutions participating.The study found that several new agents have been identified as potential candidates for cancer treatment.
