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U.S. Cancer Institute 'Megaproject' to Target Common Cancer-Driving Protein

24 June 2013 6:00 pm
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National Cancer Institute

Harold Varmus

It may be dealing with the worst budget crunch in its history, but that is not stopping the National Cancer Institute (NCI) from doing new things. Today, NCI officials outlined a plan to bring together the agency's contract lab in Frederick, Maryland, and outside researchers to find ways to block a mutated protein that drives growth in one-third of all cancers but was thought impossible to "drug" until now.

The RAS project, as NCI is calling it, will not entail huge amounts of money—just $10 million that will be reprogrammed from other work at NCI's Frederick National Laboratory for Cancer Research. But it will attempt to draw in the hundreds of extramural researchers who now study this protein and its gene to work together in what NCI Director Harold Varmus calls a "megaproject." The goal: "Finally after 30 years of knowing how important RAS is in cancer, to actually produce some outcomes that are helpful to patients," said Varmus today at a joint meeting today of his National Cancer Advisory Board and Board of Scientific Advisors.

RAS, for rat sarcoma, is a family of genes whose proteins transmit signals that allow cells to grow and survive. RAS is mutated in about 33% of cancers, including 95% of pancreatic tumors. Drug companies had long ago given up on targeting RAS, however, because it doesn't have an obvious pocket, or binding site, that a drug could fit into to block its activity, says Frank McCormick, who recently stepped down as director of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, to spend half his time directing NCI's RAS project.

Researchers have begun to find some weak spots in RAS, however, and NCI now thinks it is time for a coordinated attack on this protein. The project is part of an overhaul of the $250-million-a-year Frederick operation run by Science Applications International Corporation (SAIC) that Varmus launched after he became NCI director 3 years ago. A new advanced technologies lab will become the "hub" by moving about $10 million in work that now supports NCI's intramural program to the RAS project, said David Heimbrook, CEO of SAIC-Frederick. This lab will conduct research and also provide materials such as monoclonal antibodies, cell lines, and mice to companies and academic researchers. These groups will be the "spokes" of the program, Heimbrook said.

The actual work entails five specific projects. One will determine the structure of mutant KRAS proteins, the most common form of RAS, when it interacts with molecules within cells. A second project will build on new strategies for blocking KRAS, such as novel peptides. A third project will use imaging and screening methods to identify and disrupt the complexes that KRAS forms within cells. A fourth goal is to map the surface of cells with KRAS mutations because this could suggest proteins or peptides that could be targeted with antibodies or nanoparticles. Finally, for a fifth project, NCI wants to use so-called synthetic lethal screens, which use tools such as siRNA (molecules that block gene transcription) to discover combinations of proteins that cancer cells with mutated RAS need to survive.

Also key to the project, McCormick said, is "the idea of building a RAS community." He and others talked about "crowdsourcing," for example, by posting a problem on a website and inviting the community to comment.

The advisers were enthusiastic about the project and voted to move ahead, although they had some questions, for example, about how intellectual property agreements would work. William Sellers of Novartis said that the RAS project could serve as a model for tackling other proteins that aren't easy to block with a drug. It could also attract researchers who wouldn't otherwise be interested because the problem is "old" and won't result in a paper in Science or Nature, Sellers said. "For all those reasons, it's fantastic."

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