Mechanism of Action by mTOR Kinase Inhibitors in Colorectal Cancer

描述（由申请人提供）：结直肠癌（CRC）是最常见的人类恶性肿瘤之一，在癌症相关死亡中居第二位，在包括美国在内的发达国家甚至更为普遍。CRCs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改善CRC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PI 3 K下游。PI 3 K-哺乳动物/机械TOR（mTOR）途径在人类癌症中经常被过度激活，导致不受控制的癌症生长，这是主要的癌症药物靶标。mTOR形成两种不同的多聚体蛋白复合物mTORC 1和mTORC 2，这两种复合物都是癌细胞生长、增殖和存活所需的。大环内酯雷帕霉素和雷帕霉素类似物（rapalogs）是部分mTOR抑制剂，对主要人类癌症具有有限的功效。最近，mTOR激酶抑制剂（mTKI）已成为第二代mTOR靶向治疗剂。早期研究表明，mTKI确实对几种雷帕霉素耐药肿瘤模型有效。因此，大量mTKI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。尽管取得了初步进展，但仍然存在重大挑战。迄今为止，对其作用机制的研究很少。此外，还没有关于对这类新药的内在或获得性耐药性的研究报告。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。初步的研究结果有力地支持了我们的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。 公共卫生相关性：结直肠癌（CRC）是人类最常见的恶性肿瘤之一，在癌症相关死亡中居第二位，在包括美国在内的发达国家甚至更为普遍。CRCs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改善CRC患者的死亡率。雷帕霉素靶蛋白（TOR）是一种保守的PI 3 K相关激酶，是细胞生长和存活的关键调节因子。哺乳动物TOR（mTOR）途径在人类癌症如CRC中经常被过度激活，导致不受控制的癌症生长和增殖，使得TOR成为高度期望的癌症药物靶标。大环内酯类雷帕霉素和雷帕霉素类似物（雷帕霉素类似物）在临床上用于治疗几种不同的人类疾病，包括晚期肾细胞癌。然而，雷帕霉素类似物只是部分mTOR抑制剂，除了肾癌和其他几种罕见的肿瘤外，对主要的人类癌症不是很有效。最近，已经开发了第二代抗mTOR药物，称为mTOR激酶抑制剂（mTKI）。临床前研究表明，它们确实是比雷帕霉素类似物更有效的抗癌药物。因此，大量mTKI化合物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凸显了它们的治疗潜力。尽管取得了初步进展，但仍然存在重大挑战。迄今为止，尚未探索mTKI对CRC的作用，并且缺乏对其作用机制的理解。此外，几乎没有关于这些药物的耐药性的研究，这对这些药物的临床开发至关重要。这个应用程序将解决这些至关重要的问题。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，并改善结直肠癌的治疗。

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.