Targeting Cell Signaling in lung cancer to enhance therapeutic efficacy

靶向肺癌细胞信号转导以增强治疗效果

• 批准号: 8116326
• 负责人: Fadlo Raja Khuri
• 金额: $ 14.73万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-20 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116326
• 关键词: Biological; Biological Markers; Biology; Biostatistics Core; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Clinical Trials; Diagnosis; Farnesyl Transferase Inhibitor; Goals; International; Left; Lung; Malignant neoplasm of lung; Molecular Analysis; Mutate; Neoadjuvant Therapy; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Proteins; Resistance; Role; STK11 gene; Sampling; Signal Pathway; Signal Transduction; Spain; Taxane Compound; Testing; Therapeutic; Translating; Treatment Efficacy; Tumor Suppressor Genes; United States; Woman; cancer cell; cancer therapy; chemotherapy; docetaxel; improved; lung Carcinoma; mTOR protein; men; novel; novel strategies; outcome forecast; programs; taxane; tumor

DESCRIPTION (provided by applicant): Lung carcinoma is the leading cause of cancer-related death in men and women in the United States. Despite advances in understanding the biology of lung cancer and introduction of several novel agents, 5 year survival remains at a dismal 15%. In order to enhance therapeutic strategies, we propose to target aberrant cell signaling in lung cancers with a primary focus on the mTOR pathway. Our program consists of 4 interconnected projects and 3 primary cores. The program projects include exploration of the mammalian target of rapamycin (mTOR) axis proteins and their importance in prognosis in lung cancer (primary aim - project 1), along with translating these biological findings into therapeutic advances in lung cancer patients alone and in combination with docetaxel. Project 2 targets LKB1, a tumor suppressor gene known to be inactivated or mutated in lung cancer, and its role as a key regulator of taxane-sensitivity and TOR pathway signaling. Project 3 examines the synergy between taxanes and farnesyl-transferase inhibitors and studies the mechanisms underlying synergy and resistance to this combination. Project 4 examines the 14-3-3 protein, key regulators of the mTOR axis (especially Akt), while testing a potential application of inhibiting the 14-3-3 function for enhancing lung cancer therapy. The projects are ably supported by an administrative core, a lung pathology and molecular analysis core, and biostatistics core. It contains 3 active clinical trials and assessment of biomarkers from the Neoadjuvant Trial of Chemotherapy Hope (NATCH) being conducted in Spain. The ultimate goal of this program project is three-fold: 1) to enhance efficacy of existing agents (taxanes); 2) to study novel signaling pathways that can be regulated by molecules in clinical trials (farnesyl-transferase inhibitors); 3) to develop completely novel approaches to lung cancer therapy through modulating LKB1 and 14-3-3 functions. Lung cancer is the leading cause of cancer-related death in men and women, both in the U.S. and worldwide. Only 15% of lung cancer patients are alive five years after diagnosis, even with new drugs. The proposed program consists of four interconnected projects, supported by three cores. We hope to improve lung cancer therapy by better understanding how lung cancer cells communicate, through the process called cell signaling. We will study these cell signaling pathways and how several drugs interfere with them, so that cancer cells cannot communicate and reproduce. We will also study tumor samples from a large international clinical trial and from our own clinical trials. We believe that this project can make important advances in determining which patients will do well with which therapies. We also hope to find new drugs that only target cancer cells and their altered signaling pathways, leaving healthy cells alone.

描述（由申请人提供）：肺癌是美国男性和女性癌症相关死亡的主要原因。尽管对肺癌生物学的理解取得了进展，并引入了几种新型药物，但5年生存率仍然只有15%。为了增强治疗策略，我们建议靶向肺癌中的异常细胞信号传导，主要关注mTOR通路。我们的计划包括4个相互关联的项目和3个主要核心。该计划项目包括探索哺乳动物雷帕霉素靶（mTOR）轴蛋白及其在肺癌预后中的重要性（主要目的-项目1），沿着将这些生物学发现转化为肺癌患者单独和与多西他赛联合治疗的治疗进展。项目2针对LKB 1，一种已知在肺癌中失活或突变的肿瘤抑制基因，及其作为紫杉烷敏感性和TOR通路信号传导的关键调节因子的作用。项目3研究紫杉烷和法尼基转移酶抑制剂之间的协同作用，并研究协同作用和耐药性的机制。项目4研究了mTOR轴（特别是Akt）的关键调节因子14-3-3蛋白，同时测试了抑制14-3-3功能以增强肺癌治疗的潜在应用。这些项目得到了行政核心、肺部病理学和分子分析核心以及生物统计学核心的有力支持。它包含3项活跃的临床试验和来自西班牙正在进行的化疗希望新辅助试验（NATCH）的生物标志物评估。该计划项目的最终目标有三个方面：1）增强现有药物（紫杉烷类）的疗效; 2）研究可通过临床试验中的分子（法尼基转移酶抑制剂）调节的新型信号通路; 3）通过调节LKB 1和14-3-3功能开发全新的肺癌治疗方法。肺癌是男性和女性癌症相关死亡的主要原因，在美国和世界范围内都是如此。只有15%的肺癌患者在诊断后五年内存活，即使使用新药。该计划由四个相互关联的项目组成，由三个核心支持。我们希望通过更好地了解肺癌细胞如何通过称为细胞信号传导的过程进行交流来改善肺癌治疗。我们将研究这些细胞信号通路，以及几种药物如何干扰它们，使癌细胞无法通信和繁殖。我们还将研究来自大型国际临床试验和我们自己的临床试验的肿瘤样本。我们相信，该项目可以在确定哪些患者将在哪些治疗中表现良好方面取得重要进展。我们还希望找到只针对癌细胞及其改变的信号通路的新药，而不影响健康细胞。