Lung Cancer Drivers and Dependencies as Therapeutic Targets

肺癌驱动因素和依赖性作为治疗目标

基本信息

批准号：
8720709
负责人：
SCOTT W. LOWE
金额：
$ 35.76万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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/8720709
关键词：
17p Address Adenocarcinoma Affect Alternative Splicing Americas Automobile Driving Biochemical Biological Breast Cancer Etiology Caring Cessation of life Chromosomal Loss Chromosomes Chromosomes, Human, Pair 8 Clinic Collaborations Colon Carcinoma Combined Modality Therapy Data Dependence Dependency Development Drug Combinations Drug Targeting Drug resistance Epidermal Growth Factor Receptor Event Foundations Genes Genetic Genomics Goals Human KRAS2 gene Lesion Lung Lung Adenocarcinoma Maintenance Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of prostate Medicine Metastatic malignant neoplasm to brain Missense Mutation Mus Mutation Neoplasm Metastasis New Agents Non-Small-Cell Lung Carcinoma Oncogene Proteins Oncogenes Oncogenic Pathway interactions Persons Pharmaceutical Preparations Point Mutation Protein p53 Proteins RNA Interference Recording of previous events Recurrence Renal carcinoma Research Personnel Resistance Role Series Signal Transduction TP53 gene Technology Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Work arm attenuation base cancer therapy gain of function improved in vivo inhibitor/antagonist innovative technologies insight lung Carcinoma lung carcinogenesis mouse model mutant new therapeutic target novel outcome forecast prevent prognostic programs resistance mechanism response therapeutic target tool tumor tumor progression tumorigenesis

项目摘要

The recent identification of recurrent genetic alterations in specific cancer genes has led, through biological and biochemical analyses, to new molecularly-targeted therapies for lung cancer that have shown promise in the clinic. Still, while genomic studies continue to identify lesions of potential therapeutic relevance to cancer, functional studies, which are historically slow, are required to validate these as potential targets and develop strategies to exploit them for therapeutic benefit. Among the most prominent genomic alterations occurring in NSCLC are point mutations leading to RAS oncoprotein activation, mutation and chromosomal losses involving the p53 tumor suppressor locus on chromosome 17p, and large deletions affecting the short arm of chromosome 8 (8p). These alterations have been known for many years and often occur in the same tumors, yet precisely how they contribute to lung cancer development and how they can be exploited remains unknown. The goal ofthis project is to understand the biological and mechanistic impact of KRAS, p53, and 8p alterations on the initiation and maintenance of lung cancer, and to initiate efforts to exploit their alteration for therapeutic purposes. The project's co-investigators have a history of collaboration and collective expertise in tumor suppressor genes, mouse modeling, and drug resistance mechanisms. Here they will apply genomic information obtained from human lung cancers to inform functional studies in mice, exploiting innovative technologies to characterize biological impact of known and novel lesions on lung carcinogenesis. Building on substantial preliminary data, the project will study effectors that are required for tumor maintenance in EGFR and KRAS driven lung cancers (alone and in combination with targeted drugs), explore the action of p53 in RAS limiting lung carcinoma development, and begin to characterize new genetic lesions that drive lung carcinogenesis. The project imports new mouse models and technologies into the program, and interacts with, and benefits from, each ofthe other projects and cores. Successful completion ofthe proposed work will provide a critical foundation for improving prognostic tools and developing new targeted therapeutic strategies with new agents or drug combinations.

最近对特定癌症基因中反复发生的遗传改变的鉴定已经通过生物学方法和生化分析，以治疗肺癌的新分子靶向疗法已显示出希望诊所。尽管如此，虽然基因组研究仍在继续识别与癌症具有潜在治疗相关性的病变，功能研究历来进展缓慢，需要验证这些作为潜在目标并开发利用它们获得治疗益处的策略。其中最显着的基因组改变发生在 NSCLC 是导致 RAS 癌蛋白激活、突变和染色体丢失的点突变涉及 17p 号染色体上的 p53 肿瘤抑制基因座，以及影响短臂的大缺失 8 号染色体 (8p)。这些改变多年来一直为人所知，并且经常发生在相同的肿瘤中，但它们究竟如何促进肺癌的发展以及如何利用它们仍然存在未知。该项目的目标是了解 KRAS、p53 和 8p改变对肺癌发生和维持的影响，并开始努力利用它们的改变出于治疗目的。该项目的联合研究人员有着合作和集体的历史肿瘤抑制基因、小鼠模型和耐药机制方面的专业知识。在这里他们将应用从人类肺癌中获得的基因组信息为小鼠的功能研究提供信息，利用表征已知和新病变对肺癌发生的生物学影响的创新技术。该项目将在大量初步数据的基础上研究肿瘤所需的效应器 EGFR 和 KRAS 驱动的肺癌的维持（单独或与靶向药物联合），探索 p53 在 RAS 中限制肺癌发展的作用，并开始表征新的特征导致肺癌发生的基因损伤。该项目将新的小鼠模型和技术引入程序，并与其他每个项目和核心进行交互并从中受益。成功的完成拟议的工作将为改进预测工具和使用新药物或药物组合开发新的靶向治疗策略。