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Facilitating Research, Fueling Collaboration: Dr. Frank McCormick on the RAS Initiative

, by NCI Staff

Frank McCormick, Ph.D.

Frank McCormick, Ph.D., RAS National Program Advisor, Professor Emeritus, UCSF Helen Diller Family Comprehensive Cancer Center

Frank McCormick, Ph.D., leads the NCI-sponsored RAS Initiative at the Frederick National Laboratories for Cancer Research (FNLCR). In this interview, Dr. McCormick talks about the history, the challenges, and the future of RAS research.

What led you to become interested in RAS biology?

I started working on RAS in 1984. I was fascinated by the fact that a mutant RAS protein with only one amino acid change could cause cancer. It was remarkable that such a subtle change at the molecular level could have such a large effect.

People have been interested in RAS since the 1960s, but the problem of developing drugs to target RAS appeared to be intractable years ago, and many researchers abandoned it to study other things.

In the field of cancer drug development, the last 20 years have focused on targeting protein kinases, which are druggable. Kinases are enzymes that catalyze specific cellular biochemical reactions, and they can be targeted with small molecule inhibitors that lodge themselves in the enzyme’s active site and block it.

RAS is different because it isn’t a typical catalytic enzyme with a complex active site. Rather, it functions as an on-off switch to control a whole suite of downstream cellular signaling pathways. Some mutant forms of RAS are stuck in the “on” position, leading to cancer. The RAS protein isn’t druggable the way that protein kinases are—a different approach is required to interfere with its activity.

But with new technologies and tools, researchers can now do experiments in the lab that were impossible just a few years ago. New biochemical and cell-based assays, bioinformatics tools, and imaging technologies are allowing scientists to develop a more detailed understanding of RAS biology, which is the foundation for developing clinically relevant therapeutic approaches.

In 2013 Dr. Varmus decided that the time was right to renew our effort to advance RAS-targeted cancer therapies. Thus, the RAS Initiative was born. This initiative, funded at $10 million annually, outlines specific questions about fundamental RAS biology that need to be answered and supports the RAS research community in accelerating discovery and building the foundation for drug development.

What unique value does the RAS Initiative bring to the field of RAS research?

The RAS Initiative is unique in that we are not doing discovery research, nor are we developing drugs. Instead, we are bridging the middle ground between basic and clinical research and filling knowledge gaps in the field, such as the still-poor understanding of the structure of RAS mutant proteins, and elucidating the dynamic signaling networks in which RAS is embedded.

We’re in a unique position to create research infrastructure and to facilitate interaction and collaboration within the research community—by sharing reagents and protocols, by crowdsourcing problem-solving on the RAS blog, and by organizing workshops and meetings. The RAS Initiative is also in a unique position to build bridges between academic institutions and pharmaceutical companies to accelerate drug development.

So what are you doing to build infrastructure and improve collaboration on RAS-related research?

Developing a solid foundation of RAS biology to facilitate the development of drugs targeting RAS-driven cancers is a daunting challenge that needs to be addressed with a concerted effort.

The RAS Initiative has used a variety of approaches to generate interaction within the RAS research community. Workshops are held at the FNLCR and at meetings such as the American Association for Cancer Research. A program announcement for RAS-related research has been created to consider RAS-related grant proposals from the extramural community.

Also, two postdoctoral fellowships were recently created to support postdoctoral researchers working on RAS. We’ve established collaborations with about a dozen pharmaceutical companies to work on assays and screens. With the available technologies and the community’s renewed interest in solving the RAS problem, I am confident that we will develop promising therapeutic approaches to treat RAS-driven cancers in the coming years.

Can you describe the areas of investigation under the RAS Project, and the different approaches that are being used to develop therapies for RAS-driven cancers?

There are several ongoing RAS research projects at FNLCR. One of the Initiative’s priorities is to elucidate the structure of the RAS oncogenic mutant proteins interacting with the downstream signaling protein, RAF. Understanding this structure is the foundation for developing drugs that can disrupt this interaction.

The study of RAS structure and function is complicated by the fact that RAS works only when it is associated with a cell membrane—so its biochemistry is difficult to study in a test tube. Researchers at FNLCR are developing ways to study RAS in the context of the cell membrane with which it interacts. Interfering with how RAS organizes itself in the membrane could be a therapeutic approach.

RAS investigators are also using biochemical and cell-based assays to screen for compounds that block RAS activity. Biotechnology and pharmaceutical companies are particularly interested in this avenue of investigation as a foundation for drug development. Finally, RAS investigators are identifying proteins on the surface of RAS-mutant cancer cells that could be targeted by the immune system and used to develop new immunotherapies.

What are some intermediate successes of the RAS project?

Over the years, drugs have been developed that target signaling molecules downstream of RAS, thus addressing the RAS problem indirectly. But some recent findings show that the community is gaining ground on RAS itself.

The most exciting recent finding is the result of work by a team led by Kevan Shokat, Ph.D., of the University of California at San Francisco and a Howard Hughes Medical Institute investigator.

Dr. Shokat’s team reported a significant breakthrough in a study published in Nature in November 2013, the discovery of a binding site, or “pocket,” in mutant KRAS proteins. A chemical compound the group designed fits inside this pocket and showed efficacy in a mutant-KRAS lung cancer cell line. This RAS inhibitor is being used as a template for further drug development.

In the long haul, the success of the RAS Initiative will be measured by its ability to facilitate and accelerate the drug discovery and development process in the RAS community.

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