NOVEL RAS ANTAGONISTS FOR TREATMENT OF HUMAN CANCER

致癌基因编码蛋白质，诱导细胞发生恶性转化。致癌Ras蛋白存在于90%的胰腺癌和1/3的人类癌症中。Thyreos公司已经获得许可的药物可以通过取代Ras在细胞中的锚定位点来灭活Ras。这些药物抑制裸鼠生长的ras依赖性人肿瘤。在导致肿瘤消退的剂量下没有毒性作用。在FDA注册Ras拮抗剂用于癌症治疗是Thyreos的主要长期目标。该拨款的具体目的将开始这一过程：我们将建立在新型环糊精中溶解拮抗剂的程序，以便它们可以口腔和肠外给药。研究将在两种新发现的环糊精输送系统之间进行选择。这些任务的完成将导致毒理学和1期临床试验。目前，市场上还没有Ras拮抗剂，其他公司开发的拮抗剂与Thyreos的作用机制有很大的不同。拟议的商业应用：Ras拮抗剂是本次拨款的主题，如果临床试验显示其有效，将在FDA注册并在美国上市。这些药物对癌症治疗的吸引力在于它们没有传统化疗的所有副作用。预计这些药物可用于治疗多达三分之一的人类肿瘤。它们在治疗胰腺癌方面可能特别有效，胰腺癌是美国癌症死亡的第三大原因

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.