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The RAS Program aims to find ways of targeting the gene family known as RAS. More than a third of all human cancers, including a high percentage of pancreatic, lung, and colon cancers, are driven by mutations and possibly amplification (increased copies) of RAS genes. Thus far, attempts to develop drugs that block RAS function have been largely unsuccessful. Therefore, NCI launched the RAS Program to address this critical challenge in cancer treatment.
The RAS gene family—which includes KRAS, HRAS, and NRAS—produces proteins (RAS proteins) that are involved in cell signaling. When these proteins are altered by a mutation in the gene, cells divide uncontrollably and evade signals to die. RAS mutations can also allow cells to resist available cancer therapies. Although scientists have made great strides in the last 30 years toward understanding the signaling pathways that RAS controls, many still consider RAS an "undruggable" target for cancer therapy.
Mutant RAS proteins have been challenging to target because their alterations lock them in an always "on" state, creating a situation akin to a car with an accelerator that won't release and brakes that won’t engage. However, advances in technology and new research developments have created opportunities to address this challenge. During a series of NCI-led workshops in 2013, researchers presented data suggesting that it may now be feasible to target mutant RAS proteins directly or target other unique features of RAS-driven tumors.
After extensive discussions with the cancer research community and its advisory groups, NCI established the RAS Program to explore innovative approaches for attacking the proteins encoded by mutant forms of the KRAS gene. KRAS is the most commonly mutated RAS gene in human cancer and is implicated in more aggressive disease. NCI has redirected $10 million per year toward this effort, which is based at the Frederick National Laboratory for Cancer Research’s Advanced Technology Research Facility in Frederick, MD. The national laboratory will serve as a research “hub,” connecting investigators there with colleagues working on RAS in the "spokes" of academia, the pharmaceutical industry, the biotech industry, and NCI's intramural laboratories. Dr. Frank McCormick, a leader in the RAS field and former director of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, will lead the program’s scientific efforts.
The goals of the RAS Program are to:
With these goals in mind, roughly 1,600 researchers have been invited to collaborate on program projects. (The researchers were identified through publicly available records as holding government and/or private research grants to study RAS genes and cancer.) Plans are underway to convene additional meetings and workshops and to set up a website to facilitate collaboration among scientists from diverse disciplines. The program will include a series of projects focusing on the role of mutant RAS proteins in driving cancer cells and potential ways to inhibit the proliferation of these cells.
The RAS Program involves a number of different projects.
Project 0 — Validate mutant KRAS as a target for tumor maintenance
This project will characterize which cell lines and tumors that contain mutant KRAS might be treated with KRAS ablation (i.e., elimination).
Project 1 — Identify allele-specific compounds
Researchers will determine the protein structure of mutant forms of KRAS to identify potential drug binding pockets to modulate KRAS activity or prevent interaction with important binding partners.
Project 2 — KRAS selective binding compounds
This project will explore new strategies for blocking the activity of all mutant forms of KRAS by altering their locations in the cell.
Project 3 — Disrupting KRAS complexes
Using cell imaging and other tools, researchers hope to identify and disrupt protein complexes formed by mutant KRAS proteins.
Project 4 — Cell surface mapping
This project will map the surface of cells with KRAS mutations as a way to discover proteins or protein fragments that could be targeted with antibodies or nanoparticles.
Project 5 — Next-generation synthetic lethal screens
Researchers will use novel screens to identify proteins that are essential for the survival of cancer cells that have mutated KRAS genes.
Project 6 — Production and validation of reference reagents
This project will provide RAS investigators with qualified and standardized reagents.
For more information, email SolveRAS@nih.gov