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

基本信息

批准号：
8508219
负责人：
STEVEN ZHENG
金额：
$ 4.99万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508219
关键词：
Address Animal Model Antineoplastic Agents Biological Markers CCI-779 Cancer Cell Growth Cancer Patient Cancer cell line Cell Survival Cell model Cessation of life Clinic Clinical Clinical Drug Development Clinical Trials Colorectal Cancer Data Developed Countries Development Drug Binding Site Drug Targeting Drug resistance Drug-sensitive FDA approved Feedback Future Generations Genetic Heterogeneity Growth Growth Factor Human IRS1 gene Lead Macrolides Malignant Neoplasms Maps Mediating Modeling Mutation Nutrient Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Pre-Clinical Model Protein Kinase Proto-Oncogene Proteins c-akt Renal Cell Carcinoma Renal carcinoma Reporting Research Resistance Resolution Role Signal Transduction Sirolimus Speed Structure Testing Therapeutic Yeast Model System cancer cell cell growth clinical practice design drug discovery drug sensitivity human FRAP1 protein human disease improved inhibitor/antagonist insight kinase inhibitor mTOR inhibition mTOR protein mortality neoplastic pre-clinical preclinical study protein complex response success therapeutic target treatment strategy tumor yeast genetics

项目摘要

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.

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，在癌症相关死亡中位居第二，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主要的治疗挑战。迫切需要新的疗法来降低结直肠癌患者的死亡率。雷帕霉素靶点 (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 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。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。