Development of Novel Ras Inhibitory Agents for Cancer Therapy
Abstract
Cancer affects people from all facets of life. Research over the last several decades has revealed that cancers arise through genetic mutations. These genetic mutations activate some genes that promote cancer (oncogenes) and inactivate other genes that normally suppress cancer (tumor suppressors). Our proposal is focused on inhibiting one of the most frequently mutated genes in human cancer, called Ras. Ras normally functions in promoting the growth of cells when active. Mutations in Ras, which are present in nearly 30% of human cancers, lead to Ras being active at all times resulting in improper growth promoting signals. This application specifically focuses on the Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of colorectal cancers and pancreatic cancers, but is also relevant to blood cancers, melanomas, and myeloproliferative disorders, all of which are characterized by the presence of activating mutations in Ras. Our proposed studies will fill a gap in cancer treatment "that may affect the general population but have a particularly profound impact on military health." Given the preponderance of Ras mutations in human cancers, coupled with the fact that Veterans have a five- to sevenfold increased incidence of Ras mutant cancers, our studies are particularly relevant to the goals of the PRCRP. While there has been a long-standing interest in developing inhibitors to mutant Ras, efforts thus far have been unsuccessful. Our studies propose a novel approach to develop highly specific and selective inhibitors to the mutant forms of Ras present in tumors. Our strategy will block the mutant forms of Ras in tumors without interfering with normal forms of Ras present in non-tumor cells. This approach, in theory, will lack the undesirable side effects often seen with drugs targeting Ras in tumors. Our proposal will create designer proteins, termed "monobodies," to selectively inhibit mutant Ras proteins present in cancer cells. Monobodies represent a novel approach for Ras inhibition as these highly selective agents can be designed with exquisite specificity to the cancer-causing Ras proteins without reacting to normal Ras or any other protein in normal cells. Thus, we predict that these new anti-Ras agents will provide a potential unique therapeutic treatment for cancers bearing Ras mutations. Indeed, current research indicates that cancers with mutant Ras are dependent on mutant Ras for their continued survival. Therefore, these novel anti-Ras agents should provide a potential useful therapy for treating Ras-mutants cancers. Our proposed studies represent a proof-of-concept proposal to first isolate monobodies specific to Ras mutants. We will test the efficacy of these anti-Ras monobodies to selectively block mutant Ras in tumor cell lines without affecting normal cells. If successful, this approach would benefit a large number of cancer patients with tumors bearing Ras mutations, which account for nearly 30% of cancer patients. While our proposal will not result in direct clinical benefit in the timeframe of this proposal, we are cautiously optimistic that we will be successful in developing these new tools to specifically and selectively inhibit mutant Ras cancers in vitro within the timeframe of this proposal. Future studies over the next several years will then be necessary to test whether such inhibitors can be successfully moved into the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510174
Entities
People
- John O Bryan
Organizations
- United States Army
- University of Illinois at Chicago