It started as an ambitious shot in the dark, a plunge into the scientific unknown. But the National Cancer Institute RAS Initiative has quickly helped to reverse the field’s perspective on a problem long considered unsolvable.
When the RAS Initiative was founded in 2013, researchers studying mutated RAS proteins (cancer-causing variants of the three common RAS molecules in humans) were decentralized, scattered across government and academic laboratories. Most major pharmaceutical companies, meanwhile, had suspended or avoided drug development for RAS-related cancers because of the resources required and low chance of success.
Due to scientific limitations at the time, even the Initiative had no obvious path to better understanding the mutant proteins’ behavior in human cells or finding treatments for the thousands of RAS-related cancers. But the fledgling project headquartered at and led by the Frederick National Laboratory for Cancer Research soon began to turn heads.
Through an open, collaborative model and the weight of the National Cancer Institute, it created a united, international RAS research community. Its aspirational goals and early progress, along with headway made by other groups, helped to reignite interest and inspire laboratories and pharmaceutical companies to renew the search for treatments.
“When we first started, I don’t think we were aware of any major [companies] that had active programs that were trying to target RAS, and now, you probably can’t count them on fingers anymore,” said Dwight Nissley, Ph.D., the director of the Cancer Research Technology Program at the Frederick National Laboratory and the national lab’s senior scientist in the RAS Initiative.
The victories haven’t been purely philosophical, either. The Initiative has partnered with pharmaceutical and biotechnological companies, and, thanks to recent advances, several experimental drugs are now in research and development.
“You can draw a line between where we are now to getting more drugs in the clinic, and the road is really tough, but at least you can see a strategy forward,” said Frank McCormick, Ph.D., RAS National Program Advisor at the Frederick National Laboratory and professor at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.
Techniques, tools, and triumphs
For decades, some scientists declared that RAS proteins were “undruggable” because of two titanic obstacles. First, they’re smooth and ball-like, so it seemed almost impossible to target and bind them with a drug. Second, any drugs that can bind with them would optimally target only the mutants. Normal RAS proteins exist in every cell in the human body, so drugs that don’t specifically target mutants will also destroy many healthy cells, making patients severely ill or killing them.
These challenges have thwarted most previous attempts at drug development, but the Initiative is making progress because it’s “not using conventional approaches or paths that people have utilized before,” says Nissley.
Instead, scientists are investigating RAS on several fronts simultaneously. Structural biologists are modeling and scouring the chemical structure of the mutant proteins to find druggable vulnerabilities. Biologists are developing new methods and studying the proteins’ behavior. And chemists are designing new drugs, while computational chemists digitally model potential candidates and use artificial intelligence to identify the most promising ones.
As a federally funded facility, the Frederick National Laboratory is a sensible cornerstone for this all-out offensive. Few pharmaceutical companies would take such risk, and few academic laboratories could secure enough grants to fund the research.
“We take on riskier projects and take on projects which other people would run away from. We’re here to de-risk the projects,” McCormick said.
So far, the Initiative has moved a handful of drugs toward the clinic and found new insight into RAS. For instance, a team led by Dhirendra Simanshu, Ph.D., at the Frederick National Laboratory solved and published the first structure of the mutant KRAS4b protein that shows its hypervariable region, a “floppy tail” that interacts with cellular membranes and represents a new target for drugs.
Studies have also spawned an array of scientific tools. Through a crowdsourced community project, the Initiative identified all cooperating proteins in the biological pathway by which mutant RAS proteins cause cancer, then developed a large, publicly accessible, low-cost set of reagents to study it. The Frederick National Laboratory created a series of cell culture lines for modeling RAS proteins, while in a parallel effort, the National Cancer Institute helped to create an extensive antibody library for investigating cell signals in RAS-related cancer. Other projects have created new avenues for probing and drugging the “undruggable” proteins.
With this work under its belt, the Initiative’s leaders are optimistic. Nissley and McCormick believe that the central question is no longer one of how to deal with RAS but rather of what advance will come next.
“I think the best is yet to come,” McCormick said. “We’ll see a lot of big papers coming out in the next year or so.”