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: 7849568
• 负责人: Fadlo Raja Khuri
• 金额: $ 155.25万
• 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/7849568
• 关键词: Targeting; Cell; Signaling; lung; cancer

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与癌症相关死亡的主要原因。尽管了解了肺癌的生物学和引入几种新型药物的进步，但5年生存仍然令人沮丧。为了增强治疗策略，我们建议靶向肺癌中异常细胞信号传导，主要关注MTOR途径。我们的计划由4个相互联系的项目和3个主要核心组成。该计划项目包括探索雷帕霉素（MTOR）轴蛋白的哺乳动物靶标及其在肺癌预后的重要性（主要目的-Project -Project 1），以及将这些生物学发现转化为单独的肺癌患者的治疗进展，并与多西他赛结合。项目2靶标LKB1（一种已知在肺癌中被灭活或突变的肿瘤抑制基因，及其作为紫杉烷 - 敏感性和TOR途径信号传导的关键调节剂的作用。项目3研究了紫杉烷和Farnesyl-转移酶抑制剂之间的协同作用，并研究了该组合的协同作用和抵抗力的机制。项目4研究了14-3-3蛋白，MTOR轴的主要调节剂（尤其是AKT），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，肺病理和分子分析核心以及生物统计学核心的支持。它包含3项主动临床试验和对西班牙化学疗法希望（Natch）新辅助试验的生物标志物的评估。该计划项目的最终目标是三个方面：1）增强现有代理的功效（紫杉虫）； 2）研究可以在临床试验（Farnesyl-转移酶抑制剂）中通过分子调节的新型信号通路； 3）通过调节LKB1和14-3-3功能，开发了完全新颖的肺癌治疗方法。肺癌是在美国和全球范围内男性和女性与癌症相关死亡的主要原因。诊断后五年，只有15％的肺癌患者即使使用了新药。拟议的计划由四个相互联系的项目组成，并由三个核心支持。我们希望通过更好地理解肺癌细胞如何通过称为细胞信号传导进行肺癌细胞来改善肺癌疗法。我们将研究这些细胞信号传导途径以及几种药物如何干扰它们，以使癌细胞无法进行交流和繁殖。我们还将研究大型国际临床试验和我们自己的临床试验的肿瘤样本。我们认为，该项目可以在确定哪些患者对哪种疗法的情况下取得重要的进步。我们还希望找到仅针对癌细胞及其改变信号通路的新药，而将健康细胞独立。