Despite a great deal of progress in our understanding of the biochemistry of Ras and its role in tumorigenesis, development of effective therapeutic inhibitors of Ras to date has been disappointing. Given the frequency of Ras mutations in human cancers, there is a critical need to develop targeted inhibitors of this oncoprotein for treatment of patients with Ras-positive tumors. Our proposal represents a novel approach to this challenge. We will develop high affinity reagents that specifically target the four most frequent mutant KRas alleles in human tumors.
Aim 1 will utilize the monobody platform as a method to isolate highly specific affinity reagents that target the following KRas mutant proteins: G12D, G12V, G12C, and G13D. The specificity and potency of these reagents will be determined in vitro.
Aim 2 will then determine the specificity and selectivity of these KRas mutation specific monobodies at abrogating the tumorigenic phenotype of KRas-driven tumors vs tumors driven by other oncogenes. These studies represent a novel approach toward developing highly specific Ras inhibitory reagents and thus have the potential to make a major impact on cancer therapy. In addition, this project is highly relevant to the NCI's mission of targeting Ras-dependent cancers as evidence by the recent Ras Initiative at the Frederick National Laboratory for Cancer Research.
Our studies will lead to the development of highly speci?c inhibitors of the Ras oncogene which is one of the most frequently mutated oncogenes in human cancers. Such reagents may lead to the development of novel therapeutic agents for treatment of Ras mutant cancers. Given our current success in isolation of high af?nity reagents that target speci?c Ras activation states, our current proposal represents a moderate risk project with a high potential for reward, i.e., development of novel Ras inhibitors targeted to speci?c Ras mutants. As such, these studies have the potential to make a major impact on cancer therapy.
| O'Bryan, John P (2018) Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res : |
| Khan, Imran; Spencer-Smith, Russell; O'Bryan, John P (2018) Targeting the ?4-?5 dimerization interface of K-RAS inhibits tumor formation in vivo. Oncogene : |
| Spencer-Smith, Russell; Li, Lie; Prasad, Sheela et al. (2017) Targeting the ?4-?5 interface of RAS results in multiple levels of inhibition. Small GTPases :1-10 |
| Spencer-Smith, Russell; Koide, Akiko; Zhou, Yong et al. (2017) Inhibition of RAS function through targeting an allosteric regulatory site. Nat Chem Biol 13:62-68 |
| Spencer-Smith, Russell; O'Bryan, John P (2017) Direct inhibition of RAS: Quest for the Holy Grail? Semin Cancer Biol : |
