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：
7849562
负责人：
Fadlo Raja Khuri
金额：
$ 34.78万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7849562
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 TSC2 gene Taxane Compound Testing Time Tissue Sample Tissues Treatment Efficacy Tuberous sclerosis protein complex Tumor Suppressor Genes United States Universities Upper arm analog 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) 是一种毁灭性的疾病，将影响大约 172,570 人 2005 年的美国，其 5 年生存率仍然很低，约为 15%。这哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在促进细胞周期中发挥关键作用进展和细胞增殖，并且在包括非小细胞肺癌在内的许多癌症中经常上调。雷帕霉素及其类似物，如 RAD001，是高度特异性的 mTOR 抑制剂，目前正处于研发阶段 I-II 肿瘤学临床试验。 Akt，一种因 ras 突变而频繁激活的生存蛋白人类 NSCLC 中生长因子受体的过度表达，通过正向调节 mTOR 信号传导结节性硬化症复合体 2 (TSC2)，而抑癌基因 LKB1 发生高频率突变在 NSCLC 中，负调节 mTOR 信号传导。因此，Akt 激活和 LKB1 突变都可能影响细胞对 mTOR 抑制剂的敏感性或反应。在本提案中，我们试图确定预后非小细胞肺 mTOR 轴中关键蛋白（p-Akt、p-mTOR、p-70S6K、p-4E-BP1、p-S6）的值通过从 NATCH（化疗希望新辅助疗法）获取组织并整合来治疗癌症这些生物标志物与从项目 2-5 获得的其他生物标志物一起形成分子预后模型可手术的非小细胞肺癌。然后，我们将在接受手术治疗的患者的组织样本中交叉验证该模型埃默里-温希普癌症研究所项目中的非小细胞肺癌。确认了这些的重要性后人类肺癌组织中的生物标志物，然后我们将使用这些蛋白质作为一系列新颖的生物标志物评估 mTOR 抑制剂作为可切除手术的术前生化治疗的转化临床试验 NSCLC 以及随后与多西紫杉醇联合治疗转移性疾病。通过完成这些目标，我们可以检验我们的假设，即由于频繁的 Akt 导致 mTOR 信号传导异常激活 NSCLC 中的激活和 LKB1 突变影响患者预后，并可作为治疗的合适靶点使用 mTOR 抑制剂及其与化疗的组合有效治疗 NSCLC。