Modulation of the mTOR Pathway for Lung Cancer Treatment

调节 mTOR 通路治疗肺癌

基本信息

批准号：
8518499
负责人：
Fadlo Raja Khuri
金额：
$ 25万
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：
2012-09-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518499
关键词：
5&apos -AMP-activated protein kinase 70-kDa Ribosomal Protein S6 Kinases Adjuvant Adjuvant Chemotherapy Adjuvant Study Affect Aftercare Apoptosis Apoptotic Biochemical Biological Markers Cancer Patient Carboplatin Cell Cycle Progression Cell Proliferation Cells Clinical Trials Combined Modality Therapy Disease Disease-Free Survival Frequencies Growth Factor Receptors Human In Situ In Situ Nick-End Labeling Institutes Malignant Neoplasms Malignant neoplasm of lung Measures Modeling Molecular Mutate Mutation Neoadjuvant Therapy Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Paclitaxel Pathway interactions Patients Pattern Phase Play Predictive Value Proliferation Marker Proteins Randomized Recurrence Regulation Research Personnel Resectable Resistance Role STK11 gene Series Signal Pathway Signal Transduction Sirolimus Specimen Staining method Stains Taxane Compound Testing Time Tissue Sample Tissues Treatment Efficacy Tuberous sclerosis protein complex Tumor Suppressor Genes United States Universities analog arm cancer cell cancer therapy chemotherapy docetaxel effective therapy human TSC2 protein inhibitor/antagonist mTOR protein new therapeutic target novel oncology outcome forecast overexpression prognostic programs response taxane translational clinical trial

项目摘要

Non-small cell lung cancer (NSCLC) is a devastating illness that will affect approximately 172,570 people in the United States in 2005 and for whom 5 year survival remains dismal at approximately 15%. The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in promoting cell cycle progression and cell proliferation, and is frequently up-regulated in many cancers including NSCLC. Rapamycin and its analogues, such as RAD001, are highly specific inhibitors of mTOR and are now in phase I - II oncology clinical trials. Akt, a survival protein frequently activated due to ras mutations and overexpression of growth factor receptors in human NSCLC, positively regulates mTOR signaling via tuberous sclerosis complex 2(TSC2), whereas LKB1, a tumor suppressor gene, mutates with high frequency in NSCLC, negatively regulates mTOR signaling. Thus, both Akt activation and LKB1 mutation may impact cell sensitivity or response to mTOR inhibitors. In this proposal, we attempt to determine the prognostic values of key proteins (p-Akt, p-mTOR, p-70S6K, p-4E-BP1, p-S6) in the mTOR axis in non-small cell lung cancer by obtaining tissue from the NATCH (Nee-Adjuvant Jrial of Chemotherapy Hope) and integrating these biomarkers together with others obtained from Projects 2-5 into a molecular prognostic model for operable NSCLC. We will then cross validate that model in tissue samples from patients treated surgically for NSCLC at the Emory-Winship Cancer Institute Programs. Having confirmed the importance of these biomarkers in human lung cancer tissue, we will then use these proteins as biomarkers in a series of novel translational clinical trials evaluating the mTOR inhibitor as preoperative biochemical therapy in resectable NSCLC and subsequently in combination therapy with docetaxel in metastatic disease. By accomplishing these aims, we can test our hypothesis that aberrant activation of mTOR signaling due to frequent Akt activation and LKB1 mutations in NSCLC impacts patient prognosis and serves as opportune target for effective treatment of NSCLC using mTOR inhibitors and their combinations with chemotherapy.

非小细胞肺癌（NSCLC）是一种毁灭性疾病，将影响约172,570人 2005年的美国和5年的生存仍然令人沮丧，约为15％。这雷帕霉素（MTOR）信号通路的哺乳动物靶标在促进细胞周期中起关键作用进展和细胞增殖，并且在包括NSCLC在内的许多癌症中经常被上调。雷帕霉素及其类似物（例如Rad001）是MTOR的高度特异性抑制剂，现在处于相位 I -II肿瘤学临床试验。 AKT，由于RAS突变而经常激活的生存蛋白和人类NSCLC中生长因子受体的过表达，正式调节MTOR信号传导结节硬化症复合物2（TSC2），而LKB1（肿瘤抑制基因）以高频突变在NSCLC中，负调控MTOR信号传导。因此，AKT激活和LKB1突变都可能影响细胞敏感性或对MTOR抑制剂的反应。在此提案中，我们试图确定预后在非小细胞肺中，密钥蛋白（P-AKT，P-MTOR，P-70S6K，P-4E-BP1，P-S6）的值通过从natch（化学疗法希望的Nee-Adjuvant Jrial）获得组织并整合癌症这些生物标志物以及从项目2-5获得的其他生物标志物与分子预后模型可操作的NSCLC。然后，我们将在手术治疗的患者的组织样本中跨验证该模型 NSCLC在Emory Winship Cancer Institute计划中。确认了这些的重要性然后，在人类肺癌组织中的生物标志物，我们将在一系列新型中使用这些蛋白质作为生物标志物评估MTOR抑制剂作为术前生化疗法的转化临床试验 NSCLC以及随后在转移性疾病中与多西他赛的联合疗法。通过完成这些目的，我们可以测试我们的假设，即由于频繁Akt而引起的MTOR信号的异常激活 NSCLC中的激活和LKB1突变会影响患者的预后，并成为适当的目标使用MTOR抑制剂及其与化学疗法的组合对NSCLC有效治疗。