LAUSR

The Ras oncoprotein may participate in driving half of human tumors and as such remains the single most significant therapeutic target in cancer. Attempts to develop targeted inhibitors of RAS have proved extremely challenging. We have developed a novel Ras binding molecule that blocks the ability of Ras to interact with its downstream effector components and thus down-regulates Ras signaling. We have also developed the first direct inhibitor of the RAS effector RALGDS. Both compounds suppresses the transforming activity of mutant forms of Ras as well as the wild type protein when it is over-active due to defects in the NF1 protein. The compounds have no detectable toxicity in animals and readily crosses the blood-brain barrier. They are potently active in xenograft models of Ras mediated transformation and can eradicate the ability of Ras addicted tumor cells to form tumors in animals. We propose the compounds may serve as the basis for the development of new treatments for oncogenic RAS driven tumors and for many Rasopathy symptoms. Citation Format: Geoffrey Justin Clark. Novel RAS inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6374.