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Therapeutic potential of mTOR kinase inhibitors in lung cancer

mTOR 激酶抑制剂在肺癌中的治疗潜力

基本信息

批准号：
8825457
负责人：
Shi-Yong Sun
金额：
$ 32.16万
依托单位：
EMORY UNIVERSITY
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：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8825457
关键词：
Apoptosis Biology CASP8 and FADD-like apoptosis regulating protein CDK4 gene CDKN2A gene Cancer cell line Cell Culture Techniques Cell Cycle Progression Cell Proliferation Cell Survival Cells Clinical Complex Cyclin D1 DNA Sequence Alteration Data Down-Regulation FDA approved Feedback G1 Arrest Genes Growth Human In Vitro Induction of Apoptosis Ligands Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Mus Mutation Non-Small-Cell Lung Carcinoma Nude Mice PIK3CA gene PTEN gene Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Protein Biosynthesis Protein-Serine-Threonine Kinases Proteins Raptors Renal carcinoma Reporting Role STK11 gene Signal Pathway Signal Transduction Sirolimus TNFSF10 gene Testing Therapeutic Therapeutic Agents Tumor Necrosis Factor-alpha Work Xenograft Model Xenograft procedure analog anticancer activity attenuation cancer cell cancer type cell growth human FRAP1 protein in vivo inhibitor/antagonist kinase inhibitor mTOR Inhibitor mTOR inhibition mTOR protein novel overexpression pre-clinical response therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) is a serine-threonine kinase and plays a critical role in promoting cell growth and survival, primarily through interactions with other proteins such as raptor (forming mTOR complex 1, mTORC1) and rictor (forming mTOR complex 2, mTORC2). This pathway is frequently activated in human cancers including lung cancer and thus represents an attractive cancer therapeutic target. The conventional mTOR inhibitors rapamycin and its analogues (rapalogs) are specific allosteric inhibitors of mTORC1. Although some of them are FDA-approved drugs for treatment of renal cancer, the single-agent activity of rapalogs in most other tumor types has been modest at best. Thus, great effort has been made to develop ATP-competitive inhibitors of mTOR (i.e., mTOR kinase inhibitors; TORKinibs), which inhibit function of both mTORC1 and mTORC2. The novel TORKinibs may provide additional clinical benefits since they inhibit mTORC2, which functions as an Akt S473 kinase. Indeed, TORKinibs possess promising preclinical anticancer activity. However, the activity of TORKinibs in lung cancer has not been reported or well studied. Moreover, the impact of genetic alterations on cell sensitivity to TORKinibs is unknown. In this proposal, we will test the hypothesis that TORKinibs alone or in combination with other cancer therapeutic agents will be effective in treatment of non-small cell lung cancer (NSCLC), particularly those with CDKN2A mutation or CDK4 amplification, by accomplishing three specific aims: 1) To evaluate the efficacy of TORKinibs against the growth of NSCLC cells in vitro and in vivo and their effects on repressing mTOR signaling; 2) To demonstrate the impact of genetic alteration of CDKN2A gene and its pathway on cell responses to TORKinibs; and 3) To determine whether TORKinibs cooperates with TRAIL to augment apoptosis and to exert enhance anticancer activity in NSCLC and understand the underlying mechanisms. This proposal will allow us to evaluate the therapeutic potential of the novel TORKinibs alone or in combination with others against NSCLC, and to determine the impact of genetic alteration of CDKN2A or CDK4 on cell responses to this group of agents.

描述（由申请人提供）：雷帕霉素的哺乳动物靶点（mTOR）是一种丝氨酸-苏氨酸激酶，在促进细胞生长和存活中发挥着关键作用，主要通过与其他蛋白质如raptor（形成mTOR复合物1，mTORC1）和rictor（形成mTOR复合物2，mTORC2）的相互作用。该通路在包括肺癌在内的人类癌症中经常被激活，因此代表了一个有吸引力的癌症治疗靶点。传统的mTOR抑制剂雷帕霉素及其类似物（rapalogs）是mTORC1的特异性变构抑制剂。尽管其中一些是 FDA 批准的用于治疗肾癌的药物，但雷帕霉素类似物在大多数其他肿瘤类型中的单药活性充其量是有限的。因此，人们付出了巨大的努力来开发 mTOR 的 ATP 竞争性抑制剂（即 mTOR 激酶抑制剂；TORKinibs），其抑制 mTORC1 和 mTORC2 的功能。新型 TORKinibs 可能会提供额外的临床益处，因为它们抑制 mTORC2，而 mTORC2 充当 Akt S473 激酶。事实上，TORKinibs 具有有前景的临床前抗癌活性。然而，TORKinibs 在肺癌中的活性尚未被报道或得到充分研究。此外，遗传改变对细胞对 TORKinibs 敏感性的影响尚不清楚。在本提案中，我们将通过实现三个具体目标来测试单独使用TORKinibs或与其他癌症治疗药物联合使用TORKinibs可有效治疗非小细胞肺癌（NSCLC），特别是那些具有CDKN2A突变或CDK4扩增的非小细胞肺癌（NSCLC）的假设：1）评估TORKinibs在体外和体内对NSCLC细胞生长的功效及其抑制作用 mTOR 信号传导； 2) 证明CDKN2A基因及其通路的遗传改变对TORKinibs细胞反应的影响； 3) 确定TORKinibs是否与TRAIL协同作用以增强细胞凋亡并增强NSCLC中的抗癌活性并了解其潜在机制。该提案将使我们能够评估新型 TORKinib 单独或与其他药物联合治疗 NSCLC 的治疗潜力，并确定 CDKN2A 或 CDK4 的基因改变对细胞对这组药物反应的影响。