A new hope for pancreatic cancer: cracking the KRAS code

In 1982, researchers identified KRAS, one of the first known ‘oncogenes,’ or genetic mutations that cause cancer. KRAS mutations are found in more than 90% of pancreatic cancer cases, and researchers have been working to develop therapies targeting KRAS for more than 30 years with little progress. “A degree of nihilism developed about ever being able to go after KRAS, and it’s been called it the ‘undruggable protein’,” says Olive.

That began to change about a decade ago, when scientists managed to develop compounds that could target the form of KRAS responsible for a small subset of tumors: about 1-2% of pancreatic cancers. “That’s a partial solution, but really it was inspiration for the rest of the field to come back at the problem,” says Olive.

When Mallika Singh, PhD, vice president for translational research at Revolution Medicines, told Olive the company had invented a class of inhibitors that had the potential to target all RAS mutations, he was incredulous. “My immediate reaction was skepticism,” says Olive. “But I was curious, and we quickly established a collaboration.”

Olive’s “mouse hospital”—which completely replicates the entire treatment process in mouse models—became the pre-clinical testing grounds for the new compound. Olive and Singh worked to bring together pancreatic cancer experts from other academic institutions. “By unleashing a consortium of scientists on this problem, we were able to examine active RAS inhibition in every major class of model for pancreatic cancer, and this inhibitor performed really well in all,” says Olive.

The new compound’s remarkable success in treating pancreatic cancer in multiple animal models was published earlier this year in Nature. Not only was the compound extremely effective, Olive and his team found that in the mouse models, the drug selectively targeted the tumor cells, leaving normal cells unharmed.

Phase 1 and 2 trials are open at Columbia and a planned Phase 3 registration trial in recurrent metastatic pancreatic cancer patients is expected to commence by the end of 2024. Now, Olive sees hope on the horizon. “Optimism in pancreatic cancer researchers was treated as naiveté when I started, and I think that’s changing now.”