PRECLINICAL PHARMACOLOGY OF THE ANTI-RAS DRUG, FTS

Oncogenes encode proteins that induce cell to undergo malignant transformation. Oncogenic Ras is such a protein present in 90 percent of pancreatic carcinomas and 1/3 of all human cancers. Thyreos Corporation has licensed drugs that inactivate Ras by displacement from its anchorage site in the cell membrane. These drugs inhibit Ras-dependent human tumors grown in nude mice. There are no toxic effects at doses that cause tumor regression. To register Ras antagonists with the FDA for cancer therapy is a major goal of Thyreos. The specific aims of this grant will be to complete the next steps in this process: we will continue the preclinical pharmacology on the Ras-antagonist, FTS, in nude mice with transplants of human tumors. The studies will demonstrate the dose response effects of FTS on human tumors, its synergism with standard chemotherapy, the frequency of drug administration, the maximal tolerated doses, the need for a loading dose and the duration of a drug free period. The pharmacokinetics, metabolism, distribution and excretion of FTS in mice and rats will be studied. While Thyreos completes these studies as outlined in the Specific Aims it will complete the remainder of preclinical development. Thus at the end of the Phase II grant Thyreos will be able to file an IND for a phase 1/2 study. FTS acts on a newly identified cancer target. To our knowledge there is no other drug being developed that has the same mechanism of action as FTS.