Mechanism of Action by mTOR Kinase Inhibitors in Colorectal Cancer

描述(申请人提供)：结直肠癌(CRC)是人类最常见的恶性肿瘤之一，在与癌症相关的死亡中排名第二，在包括美国在内的发达国家更为常见。癌细胞的遗传异质性使其成为治疗的主要挑战。迫切需要新的治疗方法来提高结直肠癌患者的死亡率。雷帕霉素靶标(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下游。PI3K-哺乳动物/机械性TOR(MTOR)通路在人类癌症中经常被过度激活，导致肿瘤生长失控，是主要的抗癌药物靶点。MTOR形成两个不同的多聚体蛋白质复合体，mTORC1和mTORC2，两者都是癌细胞生长、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(雷帕洛格)是部分mTOR抑制剂，对人类主要癌症的疗效有限。最近，mTOR激酶抑制剂(MTKIs)已成为第二代mTOR靶向治疗药物。早期的研究表明，mTKI确实对几种雷帕霉素耐药的肿瘤模型有效。结果，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突显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。到目前为止，关于它们的作用机制的研究很少。此外，还没有关于这种新药的内在或获得性耐药性的研究报道。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，在与癌症相关的死亡中排名第二，在包括美国在内的发达国家更为常见。癌细胞的遗传异质性使其成为治疗的主要挑战。迫切需要新的治疗方法来提高结直肠癌患者的死亡率。雷帕霉素靶标(TOR)是一种保守的PI3K相关蛋白，是细胞生长和存活的关键调节因子。哺乳动物TOR(MTOR)通路在结直肠癌等人类肿瘤中经常被过度激活，导致肿瘤生长和增殖失控，使TOR成为一种非常理想的抗癌药物靶点。大环内酯类雷帕霉素及其类似物(雷帕洛格)在临床上被用于治疗几种不同的人类疾病，包括晚期肾癌。然而，拉帕洛格只是部分mTOR抑制剂，除了肾癌和其他几种罕见的肿瘤外，对人类主要癌症并不是很有效。最近，第二代抗mTOR药物被称为mTOR激酶抑制剂(MTKIs)已经被开发出来。临床前研究表明，它们确实是比拉帕洛格更有效的抗癌药物。因此，大量的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突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。到目前为止，mTKIs对CRCs的影响尚未被探索，对其作用机制也缺乏了解。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。这项申请将解决这些至关重要的问题。该项目的顺利完成将对这类新型抗肿瘤药物的临床开发产生重大影响，并提高结直肠癌的治疗水平。

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.