APPROACH FOR COLON CANCER THERAPY USING APC PEPTIDES

本申请的广泛的长期目标是减少电流 结肠直肠癌（CRC）的高发病率和死亡率， 治疗 许多结肠恶性肿瘤的发展。 这一关键事件， 腺瘤性结肠息肉病（APC）基因突变，与 大多数（80%）形式的散发性CRC的发展， CRC肿瘤发生中的步骤。 APC突变也会导致家族性腺瘤性 息肉病（FAP）是一种遗传性疾病， 受影响个体的CRC。 在FAP中，APC突变导致 结肠隐窝上皮细胞过度增殖，可能死于 突变的APC基因无法抑制细胞生长。 尽管 强有力的证据将APC突变与CRC联系起来，并表明APC 抑制体内和体外结肠细胞的生长， APC调节细胞功能的途径才刚刚开始 有待阐明。 因为APC似乎与特定的细胞 蛋白质，它已被假定，这是通过这些相互作用， APC抑制细胞生长。 该应用程序，这是针对 重新激活APC的生长抑制机制， 大肠癌中突变APC的作用导致的不受控制的生长 肿瘤细胞，把这个假设作为一个合理的起点。 因此，具体目标是：1）进一步表征APC的 与其他细胞蛋白质的相互作用，2）为了发现模拟 APC的功能; 3）测试这些药物的肿瘤生长抑制剂 活性使用含有APC突变的细胞。 这将涉及细胞 在正在进行的临床试验中， 遗传学研究旨在评估表型表现，维持 临床和家族史，识别和治疗受影响的个体，以及 确定APC基因型。 这项研究应提供一个机会， 将结肠癌遗传病因学研究转化为新的 通过开发模拟肿瘤的药物来治疗癌症的方法 APC功能，从而有可能逆转恶性肿瘤。 具有APC失活的癌症亚组的细胞表型。

The broad, long-term objective of this application is to reduce the current high morbidity and mortality from colorectal cancer (CRC) through improved treatment. The development of many colonic malignancies. This key event, mutation of the adenomatous polyposis coli (APC) gene, is associated with the development of most (80 percent) forms of sporadic CRC and is a early step in CRC tumorigenesis. APC mutation also causes familial adenomatous polyposis (FAP), a hereditary disease which carries a 100 percent risk for CRC in affected individuals. In FAP, APC mutation causes hyperproliferation of colonic crypt epithelial cells, presumably die to the inability of the mutant APC gene to suppress cell growth. Despite the strong evidence linking APC mutation and CRC, and indicating that APC suppresses growth of colonocytes in vivo and in vitro, the biochemical pathways through which APC modulates cellular functions are just beginning to be elucidated. Because APC appears to associate with specific cellular proteins, it has been postulated that it is through these interactions that APC inhibits cell growth. The application, which is directed at reactivating APC's growth-suppressing mechanism and ultimately reversing uncontrolled growth resulting from the effects of mutant APC in colorectal tumor cells, takes this postulate as a reasonable starting point. Accordingly, the specific aims are: 1) To further characterize APC's interaction with other cellular proteins, 2) To discover agents that mimic APC's functions, and 3) To tests these agents for tumor-growth suppressor activity using cells containing APC mutations. This will involve cell lines from FAP patients that have been established in an ongoing clinical genetic study designed to evaluate phenotypic manifestations, maintain clinical and family histories, identify and treat affected individuals, and determine the APC genotype. This study should provide an opportunity to translate research on the genetic etiology of colon cancer toward new approaches for cancer treatment through development of agents which mimic APC function and which thereby have potential to reverse the malignant cellular phenotype of the subset of cancers having APC inactivation.