Mechanism of Action by mTOR Kinase Inhibitors in Colorectal Cancer

描述（申请人提供）：结直肠癌（CRC）是最常见的人类恶性肿瘤之一，在癌症相关死亡中排名第二，在包括美国在内的发达国家更为普遍。crc的遗传异质性使其成为一个主要的治疗挑战。迫切需要新的治疗方法来提高结直肠癌患者的死亡率。雷帕霉素靶蛋白（TOR）是一种保守的蛋白激酶，是细胞生长和存活的关键调节因子，作用于PI3K的下游。pi3k -哺乳动物/机械性TOR （mTOR）通路在人类癌症中经常超激活，导致癌症生长不受控制，是癌症药物的主要靶点。mTOR形成两种不同的多聚蛋白复合物，mTORC1和mTORC2，它们都是癌细胞生长、增殖和存活所必需的。大环内酯类雷帕霉素和雷帕霉素类似物（rapalogs）是部分mTOR抑制剂，对主要人类癌症的疗效有限。最近，mTOR激酶抑制剂（mTKIs）已成为第二代mTOR靶向治疗药物。早期研究表明，mTKIs确实对几种雷帕霉素耐药肿瘤模型有效。因此，大量的mTKIs迅速进入人体临床试验。从最初的药物发现到人体临床试验的非凡速度强调了这类新型抗肿瘤药物的治疗潜力。尽管取得了早期进展，但仍存在重大挑战。迄今为止，对其作用机制的研究还很少。此外，还没有关于这类新药的内在或获得性耐药的研究报道。我们的应用程序旨在回答这些至关重要但尚未解决的问题。初步结果有力地支持了我们研究计划的合理性和可行性。该项目的成功完成将对这类新型抗肿瘤药物的临床开发产生重大影响。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the most common human malignancies and is second in cancer- related death, and is even more prevalent in the developed countries including the US. Genetic heterogeneity of CRCs renders it a major therapeutic challenge. New therapy is urgently needed to improve the mortality of CRC patients. Target of rapamycin (TOR) is a conserved protein kinase and a key regulator of cell growth and survival, acting downstream of PI3K. PI3K-mammalian/mechanistic TOR (mTOR) pathway is frequently hyper-activated in human cancers, leading to uncontrolled cancer growth, which is a major cancer drug target. mTOR forms two distinct multimeric protein complexes, mTORC1 and mTORC2, both of which are required for cancer cell growth, proliferation and survival. The macrolide rapamycin and rapamycin analogs (rapalogs) are partial mTOR inhibitors with limited efficacy toward major human cancers. Recently, mTOR kinase inhibitors (mTKIs) have emerged as the second generation of mTOR-targeted therapeutics. Early studies showed that mTKIs are indeed effective against several rapamycin-resistant tumor models. As a result, a large number of mTKIs rapidly entered human clinical trials. The extraordinary speed from initial drug discovery to human clinical trials underscores the therapeutic potential of this class of new anti-neoplastic agents. Despite early progress, significant challenges remain. Thus far there have been few studies on their mechanisms of action. Moreover, there has been no reported study on intrinsic or acquired resistance to this new drug class. Our application is aimed at answering these critically important yet unaddressed questions. The rationale and feasibility of our research plan are strongly supported by the preliminary results. Successful completion of this project should have significant impact on the clinical development of this new class of anti-neoplastic agents. PUBLIC HEALTH RELEVANCE: Colorectal cancer (CRC) is one of the most common human malignancies and is second in cancer- related death, and is even more prevalent in the developed countries including the US. Genetic heterogeneity of CRCs renders it a major therapeutic challenge. New therapy is urgently needed to improve the mortality of CRC patients. Target of rapamycin (TOR) is a conserved PI3K-related kinase and a key regulator of cell growth and survival. Mammalian TOR (mTOR) pathway is frequently hyper- activated in human cancer such as CRC, leading to uncontrolled cancer growth and proliferation, rendering TOR as a highly desirable cancer drug target. The macrolide rapamycin and rapamycin analogs (rapalogs) are used in the clinic to treat several different human diseases, including advanced renal cell carcinomas. However, rapalogs are only partial mTOR inhibitors, and except for renal cancer and several other rare tumors, are not very effective against major human cancers. Recently, a second generation of anti-mTOR drugs called mTOR kinase inhibitors (mTKIs) has been developed. Preclinical studies show that they are indeed more potent anti-cancer agents than rapalogs. As a result, a large number of mTKI compounds have rapidly entered human clinical trials. The extraordinary speed from initial drug discovery to human clinical trials underscores their therapeutic potential. Despite early progress, significant challenges remain. Thus far the effect of mTKIs toward CRCs has not been explored and the understanding of their mechanisms of action is lacking. Moreover, there is virtually no research on drug resistance to these drugs, which is critically important for clinical development of these drugs. This applicatio will address these critically important questions. Successful completion of this project should have significant impact on the clinical development of this new class of anti- neoplastic agents, and improve the treatment of colorectal cancer.