Mechanism of Action by mTOR Kinase Inhibitors in Colorectal Cancer

mTOR 激酶抑制剂在结直肠癌中的作用机制

• 批准号: 8761387
• 负责人: STEVEN ZHENG
• 金额: $ 2.43万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-03 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761387
• 关键词: Address; Antineoplastic Agents; CCI-779; Cancer Cell Growth; Cancer cell line; Cell Survival; Cells; Chronic; Clinic; Clinical; Clinical Drug Development; Clinical Trials; Colorectal Cancer; Development; Drug Targeting; Drug resistance; Event; FDA approved; Feedback; Generations; Growth; Growth Factor; Human; IRS1 gene; Macrolides; Malignant Neoplasms; Mediating; Modeling; Molecular Target; New Agents; Nutrient; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Protein Biosynthesis; Protein Kinase; Proto-Oncogene Proteins c-akt; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research; Resistance; Role; SW480; SW620; Signal Transduction; Sirolimus; Speed; System; Therapeutic; Yeasts; cancer cell; cancer therapy; cell growth; drug discovery; human FRAP1 protein; human disease; improved; inhibitor/antagonist; kinase inhibitor; mTOR protein; neoplastic; novel; preclinical study; protein complex; success; therapeutic target; tumor; yeast genetics

DESCRIPTION (provided by applicant): 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. As ATP-competitive inhibitors, there are likely to be "off-target" effect but this issue has not been carefully addressed. 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.

描述（由申请人提供）：雷帕霉素（Tor）的靶标是保守的蛋白激酶，是细胞生长和生存的关键调节剂，作用于PI3K的下游。 PI3K哺乳动物/机械性TOR（MTOR）途径经常在人类癌症中过度激活，导致不受控制的癌症生长，这是主要的癌症药物靶标。 MTOR形成了两个不同的多聚体蛋白复合物MTORC1和MTORC2，这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（Rapalogs）是部分MTOR抑制剂，对主要人类癌症有限。最近，MTOR激酶抑制剂（MTKIS）已成为第二代MTOR靶向治疗剂。早期研究表明，MTKI确实对几种抗雷帕霉素肿瘤模型有效。结果，大量MTKI迅速进入了人类临床试验。从初始药物发现到人类临床试验的非凡速度强调了这类新型抗塑性剂的治疗潜力。尽管有早期的进展，但仍有重大挑战。到目前为止，关于其作用机理的研究很少。作为ATP竞争抑制剂，可能会有“脱离目标”效应，但 这个问题尚未仔细解决。此外，还没有关于对该新药类的内在或获得性抗性的报道研究。我们的申请旨在回答这些至关重要但未解决的问题。我们的研究计划的理由和可行性得到了初步结果的强烈支持。该项目的成功完成应对这类新型抗塑料药物的临床发展产生重大影响。