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：
8624748
负责人：
Shi-Yong Sun
金额：
$ 15.47万
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 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8624748
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 Data Down-Regulation FDA approved Feedback G1 Arrest Gene Mutation 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标（MTOR）是一种丝氨酸 - 硫代激酶，主要通过与其他蛋白质（例如MTOR Complect 1，MTORC1，MTORC1）和RICTOR（MTORCORCOR）（形成MTOR Complect 2，MTOR Complect 2，MTORC2），主要是通过与其他蛋白质相互作用，在促进细胞生长和生存中起关键作用。该途径经常在包括肺癌在内的人类癌症中激活，因此代表了一个有吸引力的癌症治疗靶标。常规的MTOR抑制剂雷帕霉素及其类似物（Rapalogs）是MTORC1的特定变构抑制剂。尽管其中一些是通过FDA批准的用于治疗肾脏癌的药物，但在大多数其他肿瘤类型中，Rapalogs的单药活性充其量是适中的。因此，已经付出了巨大的努力来开发MTOR的ATP竞争抑制剂（即MTOR激酶抑制剂； Torkinibs），从而抑制MTORC1和MTORC2的功能。新型的托基尼比抑制了MTORC2，因此可以提供额外的临床益处，它起着AKT S473激酶的作用。确实，托基尼具有有希望的临床前抗癌活性。然而，尚未报告或研究过龙骨在肺癌中的活性。此外，遗传改变对细胞敏感性对托基尼的影响尚不清楚。在这项提案中，我们将检验以下假设：单独或与其他癌症治疗剂结合使用，将有效地治疗非小细胞肺癌（NSCLC），尤其是那些患有CDKN2A突变或CDK4扩增的人，通过实现三个特定的目的：1）来评估抗torkinib的效果，以抗反应的效果：1） MTOR信号传导； 2）证明CDKN2A基因的遗传改变及其途径对细胞对托基尼的反应的影响； 3）确定托基尼是否会与提高细胞凋亡的步道合作并发挥NSCLC中的抗癌活性并了解潜在的机制。该提案将使我们能够单独评估新型托基尼的治疗潜力，或与其他人对NSCLC的结合，并确定CDKN2A或CDK4遗传改变对这组药物的细胞反应的影响。