Learn About the RAS Initiative

The "Hub and Spoke" Model: the FNLCR serves as the research hub that connect research collaborators nationally and internationally.

The overarching goal of the RAS Initiative is to mobilize the cancer research community to develop ways to understand and target cancers driven by mutant RAS in an open model of collaboration among government, academic, and industry researchers. This approach is called a "hub and spoke" model. The Frederick National Laboratory for Cancer Research (FNLCR) acts as the hub that connects to the larger community of RAS researchers around the world combining efforts and creating new ways to approach the complex issue of RAS.

Portrait of Douglas Lowy

Message from Dr. Lowy

NCI's Deputy Director discusses the progress of the RAS Initiative and its goal to create a virtual network of scientists collaborating to solve the RAS problem.

The Problem with RAS Genes

Infographic that says more than 30% of all human cancers are driven by mutations of the RAS genes. It explains that 95% of pancreatic cancers have a KRAS mutation; 45% of colorectal cancers have a KRAS mutation; 35% of Lung cancers have a KRAS mutation; 30% of Acute Myeloid Leukemias have an NRAS mutation; 15% of Melanomas have a NRAS mutation; and 15% of Bladder cancers have an HRAS mutation. Dr. Frank McCormick, the RAS National Program Advisor, is quoted as saying "RAS oncogenes are the worst oncogenes."

It has been known for more than three decades that about a third of all human cancers, including a high percentage of pancreatic, lung, and colorectal cancers, are driven by mutations in RAS genes. Thus far, developing ways to block RAS gene function has been ineffective. NCI launched the RAS Initiative due to the magnitude of this challenge, as well as the potential clinical benefit. The main members of the RAS gene family— KRAS, HRAS, and NRAS—encode proteins that have a pivotal cytoplasmic role in cell signaling. When RAS genes are mutated, cells grow uncontrollably and evade death signals. RAS mutations also make cells resistant to some available cancer therapies. 

Although scientists have made great strides in the last 30 years toward understanding the signaling pathways that RAS genes control, many still consider RAS proteins as virtually “undruggable” targets for therapy.

Mutant RAS proteins have been difficult to target, in part, because they are defective in an intrinsic enzyme activity, freezing them in the “on” (GTP-bound) state (see diagram below). It is similar to a car with an accelerator that won’t release (green down arrow) and brakes that won’t engage (red up arrow). But advances in technology and improved understanding of RAS signaling and regulation have created opportunities to address this situation.

Dragging RAS Back in the Ring provides a recent review of the RAS problem. For a community view of the genes that comprise the larger RAS pathway, see our blog post, RAS Pathway v2.0.

Diagram of the RAS Pathway

RAS proteins are important for normal development. Active RAS drives the growth, proliferation, and migration of cells. In normal cells RAS receives signals and obeys those signals to rapidly switch between the active (GTP) form and the inactive (GDP form) states. Mutated RAS* is stuck in the active state, ignores signals to the contrary, and drives cells to become cancerous.

Credit: Jim Hartley, NCI RAS Initiative

RAS Initiative Origins

Since the early 1970s, the NCI has funded a contract that supports the only Federally Funded Research and Development Center (FFRDC) devoted principally to biomedical research. Located on a government campus in Frederick, MD, the FFRDC has provided a variety of laboratory services to the scientific community, performed research in response to national needs, and supervised subcontracts for the NCI for over 40 years.

In 2011, following a suggestion by the NCI’s National Cancer Advisory Board, former NCI Director Harold Varmus named the operational laboratory arm of the FFRDC Frederick National Laboratory for Cancer Research (FNLCR) and established an advisory committee (now called the Frederick National Lab Advisory Committee or FNLAC). The FNLAC recommended that the FNLCR identify and undertake important and ambitious projects in cancer research that would be difficult to pursue without an orchestrated effort.

After extensive consultation with the research community and with the FNLAC, Dr. Varmus, his NCI colleagues, and the leaders of Leidos Biomedical Research, Inc. (the current contractor for the FFRDC) launched the RAS Initiative in 2013. Existing resources within the FFRDC were redirected to establish a hub of research activity under the direction of Frank McCormick, a widely respected leader of research on RAS proteins.

Oversight

Oversight of the NCI RAS Initiative is carried out on a variety of levels. A leadership team within NCI administratively operates the program on the government side and interacts closely with the program’s leaders at the Frederick National Laboratory for Cancer Research (FNLCR) to develop program direction and evaluate progress. The Frederick National Lab Advisory Committee (FNLAC) was instrumental in approving the concept of the RAS Initiative and receives periodic updates from the Ad hoc RAS Working Group (see below). This Ad hoc group evaluates the scientific goals, direction, priorities, and progress of the hub projects at the FNLCR, as well as how the hub interfaces with industry and the extramural community.

NCI Leadership

Doug Lowry, M.D., Deputy Director, NCI

Douglas R. Lowy, M.D.
Deputy Director, NCI

Sara Hook, Ph.D., RAS Program Director, Contracting Officer Representative

Sara Hook, Ph.D.

RAS Program Officer, Contracting Officer Representative

Ed Harlow, Ph.D., Special Assistant to the NCI Director

Ed Harlow, Ph.D.

Special Assistant to the NCI Director

Frederick National Laboratory for Cancer Research RAS Leadership

Dr. Frank McCormick who directs the research efforts of the RAS Initiative at FNLCR

Frank McCormick, Ph.D., F.R.S.
RAS National Program Advisor, FNLCR and Professor Emeritus, UCSF Helen Diller Family Comprehensive Cancer Center

Ethan Dmitrovsky, M.D. Director, FNLCR

Ethan Dmitrovsky, M.D.

Director, FNLCR

Dwight Nissley, Ph.D., Director of the Cancer Research Technology Program, FNLCR

Dwight V. Nissley, Ph.D.
Director of the Cancer Research Technology Program, FNLCR

RAS Initiative Advisory Groups

Ad hoc RAS Working Group

The purpose of this working group is to provide the highest quality oversight to the technical aspects of the RAS Initiative and to provide findings and recommendations to the NFAC and the Ad hoc RAS Oversight Subcommittee.

The evaluations will include the scientific goals, direction, priorities, and timelines of the RAS research projects at the FNLCR hub. A major goal of the program is to mobilize the cancer research community to collaboratively undertake the mission of developing therapeutic strategies against KRAS oncogenes. The evaluations will also include the means by which the RAS Initiative engages the extramural community and industry, for example, through collaboration; input on funding opportunities; and sharing ideas, data, and reagents. The findings of this working group will be invaluable in assessing the progress of this “national mission,” and will provide insight for the development of new national missions.

Ad hoc RAS Working Group Co-Chairs

Kenneth J. Pienta, M.D.
The Donald S. Coffey Professor of Urology
Professor of Oncology
Professor of Pharmacology and Molecular Sciences
Johns Hopkins Hospital
The James Buchanan Brady Urological Institute
Baltimore, Maryland

David A. Tuveson, M.D., Ph.D.
Roy J. Zuckerberg Professor
Director of the Cancer Center
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York

Ad hoc RAS Working Group Members

Gideon E. Bollag, Ph.D.
Chief Executive Officer
Plexxikon, Inc.
Berkeley, California

Channing J. Der, Ph.D.
Sarah Graham Kenan Distinguished Professor
Department of Pharmacology
UNC Lineberger Comprehensive Cancer Center
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Nader Fotouhi, Ph.D.
Chief Scientific Officer
TB Alliance
New York, New York

Levi A. Garraway, M.D., Ph.D.
Senior Vice President
Global Development and Medical Affairs
Eli Lilly and Company
Indianapolis, Indiana

Nathanael S. Gray, Ph.D.
Professor, Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Professor, Cancer Biology
Dana-Farber Cancer Institute
Boston, Massachusetts

Elizabeth M. Jaffee, M.D.
Deputy Director, The Sidney Kimmel Comprehensive Cancer Center
The Dana and Albert Cubby Broccoli Professor of Oncology
Co-Director, Skip Viragh Center for Pancreas Cancer
The Johns Hopkins University
Baltimore, Maryland

Robert D. Schreiber, Ph.D.
Alumni Endowed Professor of Pathology and Immunology
Professor of Molecular Microbiology
Director, Washington University Center for Human Immunology and Immunotherapy Programs
Program Co-Leader, Tumor Immunology
Siteman Comprehensive Cancer Center
Washington University School of Medicine
St. Louis, Missouri

Roger K. Sunahara, Ph.D.
Professor of Pharmacology
Department of Pharmacology
University of California, San Diego
La Jolla, California

Matthew Vander Heiden, M.D., Ph.D.
Howard Hughes Medical Institute Faculty Scholar
Associate Professor of Biology
Koch Institute for Integrative Cancer Research
Massachusetts Institute of Technology
Cambridge, Massachusetts

Ex Officio

Lawrence J. Marnett, Ph.D.
Dean of Basic Sciences
Mary Geddes Stahlman Professor of Cancer Research
Professor of Biochemistry, Chemistry, and Pharmacology
Vanderbilt University School of Medicine
Nashville, Tennessee

Sara Hook, Ph.D.
RAS Program Officer
Contracting Officer Representative
National Cancer Institute
National Institutes of Health
Bethesda, Maryland

Contact

For general comments and questions, please email SolveRAS@nih.gov.

For partnership development, please email the Partnership Development Office, Leidos Biomedical Research, Inc./Frederick National Laboratory for Cancer Research (FNLCR) at andrew.quong@nih.gov.

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  • Posted: September 14, 2016