Modulation of the mTOR Pathway for Lung Cancer Treatment

调节 mTOR 通路治疗肺癌

• 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
• 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' -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

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人在 2005年，美国的5年存活率仍然令人沮丧，约为15%。这个 哺乳动物雷帕霉素靶点(MTOR)信号通路在促进细胞周期中的关键作用 并且在包括非小细胞肺癌在内的许多癌症中表达上调。 雷帕霉素及其类似物，如RAD001，是mTOR的高度特异性抑制剂，目前处于同一阶段 I-II肿瘤学临床试验。AKT是一种生存蛋白，由于ras突变和 生长因子受体在人非小细胞肺癌中的过表达，通过 结节性硬化症复合体2(TSC2)，而肿瘤抑制基因LKB1高频突变 在非小细胞肺癌中，负向调节mTOR信号。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。在这个提案中，我们试图确定预后 非小细胞肺mTOR轴关键蛋白(p-Akt、p-mTOR、p-70S6K、p-4E-BP1、p-S6)的表达 从自然中获取组织的癌症(Nee-adjuvant Jrial of Chemical Hope)并整合 这些生物标记物和其他从项目2-5获得的生物标记物一起进入了一个分子预后模型 可手术的非小细胞肺癌。然后，我们将在手术治疗的患者的组织样本中交叉验证这一模型 埃默里-温希普癌症研究所项目的非小细胞肺癌。在确认了这些因素的重要性之后 人类肺癌组织中的生物标记物，然后我们将使用这些蛋白质作为生物标记物在一系列新的 转化性临床试验评价mTOR抑制剂作为可切除手术的术前生化治疗 NSCLC，随后在转移性疾病中与多西他赛联合治疗。通过完成 这些目标，我们可以检验我们的假设，mTOR信号的异常激活是由于频繁的Akt NSCLC中的激活和LKB1突变影响患者预后，并成为治疗NSCLC的合适靶点 应用mTOR抑制剂及其联合化疗有效治疗非小细胞肺癌。