SBIR-STTR Award

Oncogenes encode proteins that induce cells to undergo malignant transformations. Oncogenic Ras is such a protein present in 90% 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. 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 long-term goal of Thyreos. The specific aims of this grant will begin this process: we will establish procedures that solubilize antagonist in novel cyclodextrins so that they can be administered buccally and parenterally. The studies will select between two newly discovered cyclodextrin delivery systems. Completion of these tasks will lead to toxicology and to Phase 1 clinical trials. Currently, there are no Ras antagonists on the market and the antagonists that are been developed by other companies have very different mechanism of action from those of Thyreos. PROPOSED COMMERCIAL APPLICATIONS: The Ras antagonists are the subject of this grant will be registered with the FDA and marketed in the U.S. if they are shown to be effective by clinical trials. The attractiveness of these agents for cancer treatment is that they are without all the side effects of conventional chemotherapy. It is anticipated that these drugs could be used in up to one third of human tumors. They are likely to be particularly effective in treatment of pancreatic cancer, which is the third leading cause of cancer death in the U.S.

Thesaurus Terms:
antineoplastic, cyclodextrin, drug design /synthesis /production, inhibitor /antagonist, oncogene drug screening /evaluation, oncoprotein, pharmacokinetics chemical synthesis, high performance liquid chromatography, laboratory rat

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.

Thesaurus Terms:
antineoplastic, cyclodextrin, drug design /synthesis /production, drug screening /evaluation, guanine nucleotide binding protein, inhibitor /antagonist, neoplasm /cancer pharmacology, oncogene, pharmacokinetics dosage, drug metabolism, oncoprotein athymic mouse, chemical synthesis, high performance liquid chromatography, laboratory rat