Developing new ornithine decarboxylase inhibitors to prevent skin & colon cancer

描述（由申请人提供）：多胺合成增加和炎症与上皮内瘤变有关，这是人类各种癌症发展的危险因素。鸟氨酸脱羧酶（ODC）在许多癌症细胞类型中高表达，促进生长和肿瘤形成。在癌变模型系统和肿瘤组织中，ODC活性的升高表明这种酶是化学预防的有效靶标。二氟甲基鸟氨酸（DFMO）是FDA批准的一种药物，作为一种不可逆的特异性ODC抑制剂，据报道可以防止致癌，特别是在皮肤和结肠中。然而，人体内高剂量的DFMO与不同程度的听力损失有关。通过使用BlueGene/L超级计算机的计算生物学，我们发现了至少一种ODC的小分子变抑素抑制剂，在抑制皮肤和结肠癌的发生方面，它的毒性更小，而且比DFMO更有效。在本应用中，我们建议使用最先进的技术来鉴定和测试额外的新型无毒ODC小分子抑制剂。这些方法包括使用BlueGene/L超级计算机和我们新获得的GPU系统通过计算模拟确定结合、结合亲和力、特定结合位点和由此产生的结构变化，并进行蛋白质结合实验、细胞转化实验和体内动物实验，包括2期小鼠皮肤癌变模型和APCmin小鼠模型。通过这些研究，我们将开发出更有效、副作用更小的靶向ODC药物，用于皮肤癌和结肠癌的化学预防。

DESCRIPTION (provided by applicant): Increased polyamine synthesis and inflammation are associated with intraepithelial neoplasia, which are risk factors for various types of cancer development in humans. Ornithine decarboxylase (ODC) is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated ODC activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. Difluoromethylornithine (DFMO) is an approved FDA drug that acts as an irreversible and specific ODC inhibitor, and reportedly prevents carcinogenesis, especially in the skin and colon. However, high doses of DFMO in humans are associated with various degrees of hearing loss. By using computational biology with the BlueGene/L supercomputer, we have found at least one small molecule allosteric inhibitor of ODC that is less toxic and more potent than DFMO in suppressing skin and colon carcinogenesis. In this application, we propose to use state of the art technologies to identify and test additional novel, nontoxic small molecule inhibitors of ODC. These approaches include determining binding, binding affinities, specific binding sites and resulting structural changes by computation simulation using the BlueGene/L Supercomputer and our newly acquired GPU system, and performing protein binding assays, cell transformation assays and in vivo animal experiments, including the 2-stage mouse skin carcinogenesis model and the APCmin mouse model. Through these studies, we will develop more effective agents targeting ODC with fewer side effects for the chemoprevention of skin cancer and colon cancer.