Chemoprevention of colon cancer by targeting the Wnt/beta-catenin pathway

DESCRIPTION（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第三大常见原因。apc肿瘤抑制基因的种系突变是家族性腺瘤性息肉病（FAP）的原因，apc肿瘤抑制基因是CRC发展的关键因素之一，也是Wnt/ β -连环蛋白信号通路的重要组成部分。导致Wnt/ß-catenin信号通路组成性激活的突变可导致结肠癌。Wnt(s)在调节细胞命运、增殖、迁移和死亡中具有多种作用。-连环蛋白在许多癌细胞类型中高表达，促进生长和肿瘤形成。在癌变模型系统和肿瘤组织中β -连环蛋白活性升高表明该酶是化学预防的有效靶标。通过使用BlueGene/L和GPU超级计算机的计算生物学，我们已经鉴定/合成了几种高效或具有良好抑制结肠癌发生潜力的β -catenin小分子抑制剂。在这个应用中，我们建议使用最先进的技术来继续识别、表征、测试和验证新的、无毒的-连环蛋白小分子抑制剂。我们的方法包括确定结合，结合亲和力，识别特定的结合位点，并通过使用我们的超级计算机系统计算模拟来检查由此产生的结构变化。我们将通过蛋白质结合实验、细胞转化实验和体内动物实验来验证这些抑制剂的有效性，包括异种移植模型、aom诱导的结肠癌和APCMin小鼠模型。通过这些研究，我们将开发出更有效的靶向β -连环蛋白的药物，副作用更小，用于结肠癌的化学预防。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most common cause of cancer death in the USA. Germline mutations in the apc tumor suppressor gene, one of the key players in the development of CRC and an important component in the Wnt/beta-catenin signaling pathway, are responsible for familial adenomatous polyposis (FAP). Mutations that result in constitutive activation of the Wnt/ß-catenin signaling pathway can lead to colon cancer. Wnt(s) have diverse roles in regulating cell fate, proliferation, migration, and death. beta-Catenin is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated beta-catenin activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. By using computational biology with BlueGene/L and GPU supercomputers, we have identified/synthesized several small molecule inhibitors of beta-catenin that are highly effective or have good potential to suppress colon carcinogenesis. In this application, we propose to use state of the art technologies to continue to identify, characterize, test and validate novel, nontoxic small molecule inhibitors of beta-catenin. Our approaches include determination of binding, binding affinities, identification of the specific binding sites, and examining the resulting structural changes by computational simulation using our supercomputer systems. We will validate the effectiveness of these inhibitors by performing protein binding assays, cell transformation assays and in vivo animal experiments, including xenograft models and the AOM-induced colon cancer and APCMin mouse models. Through these studies, we will develop more effective agents targeting beta-catenin with fewer side effects for the chemoprevention of colon cancer.