Ken Olive: Making a Long-Awaited Breakthrough in Pancreatic Cancer

Ken Olive grew up torn between two career options. “When I was asked in grade school what I wanted to do when I grew up, it was either a scientist or a veterinarian,” says Olive, who is now an associate professor of medicine at Columbia and a member of the Herbert Irving Comprehensive Cancer Center. Initially intending to pursue both a veterinary degree and a Ph.D., his work in cancer research as an undergraduate eventually steered him toward the scientific track, but his interest in treating disease never ended. 

In graduate school at MIT, Olive learned to genetically engineer mice in the lab of noted cancer researcher Tyler Jacks. “The focus at that time in academia was not very translational, it was on disease modeling, but translational work was what I really wanted to do,” says Olive. To pursue that, he took a postdoctoral position with physician-scientist David Tuveson, who was then at the University of Pennsylvania. 

Building a ‘mouse hospital’ for pancreatic cancer research 

“He had just made this really fantastic mouse model of pancreatic cancer, and now we needed to use it. We needed to build a mouse hospital that paralleled the structure of a human clinic; that was my first assignment,” says Olive. The idea was to take an entirely new approach to disease modeling, replicating the entire treatment process in the animal model. 

“In a hospital for humans, you walk in with symptoms, and you are diagnosed through blood work, imaging, and other tests, you are treated with surgery or medicine, and then you are monitored with more tests … so we needed all of that infrastructure for mice to figure out how the tumor was changing over time,” Olive explains. 

When it came time to establish his own lab, Olive knew he wanted to continue working on pancreatic cancer with this new approach. “It was an open, fresh opportunity to finally deploy really high quality tools against this disease that at the time was wildly understudied relative to the number of people who suffered from it,” he says. The difficulty of the problem also appealed to him. At the time, a generation of oncologists had spent their entire careers without seeing any improvement in their patients’ dismal survival rates. 

Drugging the ‘undruggable’ K-Ras protein 

New treatments developed in the past few years have begun to chip away at pancreatic cancer’s notorious lethality. Nonetheless, researchers remained frustrated, especially as they had discovered one of the primary molecular drivers of the disease decades ago: a mutation in the gene encoding K-Ras, a critical regulator of cellular signaling. Unfortunately, K-Ras research has long been where good treatment ideas go to die. “A degree of nihilism developed about ever being able to go after K-Ras, and companies 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 K-Ras 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. One company, Revolution Medicines of Redwood City, CA, managed to develop a compound that could bind and inhibit all forms of K-Ras. 

Moving from the lab to the clinic, hope is on the horizon 

Revolution Medicine’s Mallika Singh soon invited Olive to collaborate, studying the new compound in his lab’s mouse hospital. “I consider myself to be very fortunate to have ended up in the right place at the right time, at a stage of my career where we could manage the scale of work that was involved in this project,” says Olive. Urszula Wasko, one of Olive’s graduate students, was soon leading an effort that expanded to include not only the entire lab, but teams at a half-dozen other institutions as well. 

The result was a paper published recently in Nature, which describes the new compound’s remarkable success in treating pancreatic cancer in multiple animal models. Researchers were initially worried that such a drug would be poorly tolerated, since many healthy cells in the body rely on Ras proteins for their normal growth. Olive and his team found that in the mouse models, the drug selectively targeted the tumor cells, leaving normal cells unharmed. 

A phase 1 clinical trial of a related drug is also underway and plans for large-scale trials have been announced. Now, Olive is working to push the field further. “I think we’re at an inflection point in the history of the treatment of pancreatic cancer,” he says, adding that “optimism in pancreatic cancer researchers was treated as naiveté when I started, and I think that’s changing now; over the next decade, I think the improvement will continue if not accelerate.”