Novel target for therapy refractory lung tumors

治疗难治性肺部肿瘤的新靶点

基本信息

批准号：
8882940
负责人：
Ann Marie Pendergast
金额：
$ 35.88万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-08 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8882940
关键词：
ABL1 gene ABL2 gene Accounting Adenocarcinoma Biological Brain Cancer Etiology Cell Line Cessation of life Combined Modality Therapy Dasatinib Data Effectiveness Epidermal Growth Factor Receptor Evaluation FGFR1 gene Family Gene Amplification Genetic Genetic Engineering Growth Human KRAS2 gene Laboratories Large Cell Carcinoma Life Link Lung Adenocarcinoma Lung Neoplasms Malignant Epithelial Cell Malignant neoplasm of lung Messenger RNA Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes PTEN gene Pathway interactions Phosphorylation Phosphotransferases Proteins Receptor Protein-Tyrosine Kinases Refractory Regulation Reporting Role STK11 gene Signal Pathway Signal Transduction Solid Neoplasm Squamous cell carcinoma Survival Rate TP53 gene Testing The Cancer Genome Atlas Time Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Tyrosine Phosphorylation United States base bone cancer cell chemotherapy conventional therapy in vivo inhibitor/antagonist insight kinase inhibitor leukemia mRNA Expression mortality mouse model mutant novel overexpression public health relevance response targeted treatment therapy resistant tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality worldwide with a five-year survival rate of ~10 to 15%. Non-small cell lung carcinoma (NSCLC) accounts for ~80% of all lung cancer cases, and can be divided in distinct subtypes including adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma (LCC). Major drivers of lung adenocarcinoma include mutations in KRAS (~30%) and EGFR (15%), while amplification of receptor tyrosine kinases (RTKs) and loss of tumor suppressors has been linked to SCC. However, the identities of the pathways that promote the progression of ~40% of adenocarcinoma, ~60% of SCC, and the majority of LCC tumors, are currently unknown. Moreover, current therapies against EGFR and other `driver' kinases have shown to be ineffective due to variable, transient and incomplete responses. Thus, progression of lung tumors may require the activity of downstream kinases required for the regulation of tumor growth, survival and/or metastasis. Based on our recent findings we propose that candidates for such kinases are the Abl non-receptor kinases. We found that Abl kinases are up-regulated in subsets of primary human lung tumors, and demonstrate that inhibition of Abl kinases markedly impairs the growth of selected NSCLC subtypes, as well as Kras-driven lung tumors in mice. Moreover, we uncovered an essential role for Abl kinases in promoting metastases of KRAS and EGFR mutant lung cancer cells. Further, we found that inhibition of Abl kinases sensitized selected therapy-resistant lung cancer cells to targeted therapies. Our central hypotheses are that Abl kinases promote lung tumor progression and metastasis, and that inhibition of Abl kinases might be exploited for treating selected lung tumors. To test these hypotheses we propose the following specific aims: 1) Define the mechanisms by which Abl kinases promote metastasis of lung cancer cells, and evaluate the effectiveness of novel Abl kinase inhibitors in treating NSCLC metastasis. 2) Define the role of Abl family kinases in lung tumor progression using genetically engineered autochthonous Kras-driven lung cancer mouse models and pharmacological inhibition or genetic inactivation of Abl kinases. 3) Evaluate whether inhibition of the Abl kinases sensitizes selected therapy-refractory tumors to growth inhibition by targeted chemotherapies, and dissect the mechanism underlying this response. Results from this proposal will yield novel insights into the signaling networks regulated by Abl kinases in selected lung cancer cells. Further, the availability of new specific Abl kinase inhibitors as well as mouse models with conditional deletion of the Abl kinases generated in our laboratory will allow for rapid evaluation of these kinases as targets for the treatment of therapy-refractory lung cancer.

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，五年生存率约为 10% 至 15% 非小细胞肺癌 (NSCLC) 约占所有肺癌病例的 80%。，并可分为不同的亚型，包括腺癌、鳞状细胞癌 (SCC) 和大细胞癌 (LCC) 肺腺癌的主要驱动因素包括 KRAS 突变。 (~30%) 和 EGFR (15%)，而受体酪氨酸激酶 (RTK) 的扩增和肿瘤抑制因子的缺失与鳞状细胞癌有关，然而，促进约 40% 腺癌进展的途径的特性，约 60% 的 SCC 和大多数 LCC 肿瘤目前尚不清楚，而且，目前针对 EGFR 和其他“驱动”激酶的疗法已被证明由于可变的、短暂的和无效的。因此，肺肿瘤的进展可能需要调节肿瘤生长、存活和/或转移所需的下游激酶的活性，我们建议此类激酶的候选者是 Abl 非受体激酶。我们发现 Abl 激酶在原发性人类肺肿瘤的子集中上调，并证明 Abl 激酶的抑制显着损害选定的 NSCLC 亚型以及 Kras 驱动的小鼠肺肿瘤的生长。发现 Abl 激酶在促进 KRAS 和 EGFR 突变型肺癌细胞转移中的重要作用，此外，我们发现 Abl 激酶的抑制使选定的治疗耐药性肺癌细胞对靶向治疗敏感。为了检验这些假设，我们提出以下具体目标：1) 定义 Abl 激酶促进的机制。肺癌细胞的转移，并评估新型 Abl 激酶抑制剂在治疗 NSCLC 转移中的有效性 2) 使用基因工程原生 Kras 驱动的肺癌小鼠模型和药理学抑制或基因失活来定义 Abl 家族激酶在肺肿瘤进展中的作用。 3) 评估 Abl 激酶的抑制是否使选定的难治性肿瘤对靶向化疗的生长抑制敏感，并进行剖析这一反应的机制将产生对选定的 Abl 激酶调节的信号网络的新见解。此外，新的特异性 Abl 激酶抑制剂以及小鼠的可用性。我们实验室生成的条件性删除 Abl 激酶的模型将允许快速评估这些激酶作为治疗难治性肺癌的靶标。