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 的下游。 PI3K-哺乳动物/机械 TOR (mTOR) 通路在人类癌症中经常过度激活，导致癌症生长不受控制，这是主要的癌症药物靶标。 mTOR 形成两种不同的多聚蛋白复合物：mTORC1 和 mTORC2，两者都是癌细胞生长、增殖和存活所必需的。大环内酯雷帕霉素和雷帕霉素类似物（雷帕霉素类似物）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 (mTKI) 已成为第二代 mTOR 靶向治疗药物。早期研究表明，mTKI 确实对几种雷帕霉素耐药肿瘤模型有效。由此，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凸显了此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还很少。作为ATP竞争性抑制剂，可能存在“脱靶”效应，但 这个问题尚未得到认真解决。此外，还没有关于这种新药类别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研究计划的基本原理和可行性。该项目的成功完成将对此类新型抗肿瘤药物的临床开发产生重大影响。