Novel target for therapy refractory lung tumors

治疗难治性肺部肿瘤的新靶点

• 批准号: 9269186
• 负责人: Ann Marie Pendergast
• 金额: $ 35.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/9269186
• 关键词: ABL1 gene; ABL2 gene; Adenocarcinoma; Biological; Brain; Cancer Etiology; Cell Line; Cells; Cessation of life; Combined Modality Therapy; Dasatinib; Data; Effectiveness; Epidermal Growth Factor Receptor; Evaluation; FGFR1 gene; Family; Gene Amplification; Genetic; Genetic Engineering; Growth; Human; Impairment; KRAS2 gene; Laboratories; Large Cell Carcinoma; Life; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Messenger RNA; Metastatic Neoplasm to the Lung; Mus; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; PTEN gene; Pathway interactions; Pharmacology; Phosphorylation; Phosphotransferases; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Regulation; Reporting; Role; STK11 gene; Savings; 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; cancer pharmacology; cancer subtypes; chemotherapy; conventional therapy; in vivo; inhibitor/antagonist; insight; kinase inhibitor; leukemia; mRNA Expression; mortality; mouse model; mutant; new combination therapies; new therapeutic target; novel; overexpression; public health relevance; response; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth; tumor progression

 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(申请人提供)：肺癌是全球癌症死亡的主要原因，五年存活率约为10%至15%。非小细胞肺癌(NSCLC)约占所有肺癌病例的80%，可分为腺癌、鳞癌和大细胞癌。肺腺癌的主要诱因包括KRAS(~30%)和EGFR(15%)突变，而受体酪氨酸激酶(RTK)的扩增和抑癌基因的缺失与鳞癌有关。然而，促进~40%的腺癌、~60%的鳞癌和大多数LCC肿瘤进展的途径目前尚不清楚。此外，目前针对EGFR和其他“司机”激酶的治疗由于反应多变、短暂和不完全而被证明是无效的。因此，肺癌的进展可能需要调节肿瘤生长、生存和/或转移所需的下游激酶的活性。根据我们最近的发现，我们认为这类激酶的候选者是Abl非受体激酶。我们发现Abl激酶在人类原发肺肿瘤的亚型中上调，并表明抑制Abl激酶显著损害选定的NSCLC亚型的生长，以及Kras驱动的小鼠肺癌。此外，我们还发现了Abl激酶在促进KRAS和EGFR突变肺癌细胞转移中的重要作用。此外，我们还发现抑制Abl激酶可使部分耐药肺癌细胞对靶向治疗敏感。我们的中心假设是Abl激酶促进了肺癌的进展和转移，并且Abl激酶的抑制可能被用于治疗特定的肺癌。为了验证这些假说，我们提出了以下具体目标：1)明确Abl激酶促进肺癌细胞转移的机制，并评价新型Abl激酶抑制剂治疗NSCLC转移的有效性。2)通过基因工程方法构建Kras基因驱动的肺癌小鼠模型，通过药物抑制或基因失活的方法，明确Abl家族激酶在肺癌进展中的作用。3)评价ABL激酶的抑制是否通过靶向化疗使选择的治疗难治性肿瘤对生长抑制敏感，并分析这种反应的机制。这一提议的结果将对由Abl激酶调控的信号网络产生新的见解 肺癌细胞。此外，新的特异性Abl激酶抑制剂的可用性以及小鼠 我们实验室产生的ABL激酶有条件缺失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点。