Novel target for therapy refractory lung tumors

治疗难治性肺部肿瘤的新靶点

• 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
• 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; 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

 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（由适用提供）：肺癌是全球癌症死亡率的主要原因，五年生存率约为10％至15％。非小细胞肺癌（NSCLC）占所有肺癌病例的约80％，可以分为不同的亚型，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的突变（约30％）和EGFR（15％），而受体酪氨酸激酶（RTKS）的扩增以及肿瘤补充剂的丧失与SCC有关。然而，目前尚不清楚促进约40％腺癌进展的途径的身份，占SCC的60％和大多数LCC肿瘤的身份。此外，由于反应可变，瞬态和不完全的反应，针对EGFR和其他“驱动器”激酶的当前疗法已显示出无效。这是肺部肿瘤的进展可能需要调节肿瘤生长，生存和/或转移所需的下游细胞酶的活性。根据我们最近的发现，我们建议这样的替代酶是ABL非受体Tinass。我们发现，在原发性人类肺肿瘤的亚群中，ABL Tinase被上调，并证明抑制ABL Tinase明显损害了所选NSCLC亚型的生长以及小鼠KRAS驱动的肺肿瘤。此外，我们发现了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，我们发现对靶向疗法的抑制ABL激酶敏感的选择耐药性肺癌细胞的抑制作用。我们的中心假设是ABL激酶促进了肺部肿瘤的进展和转移，并且可以探索对ABL激酶的抑制作用来治疗选定的肺肿瘤。为了检验这些假设，我们提出以下特定目的：1）定义ABL激酶促进肺癌细胞转移的机制，并评估新型ABL激酶抑制剂在治疗NSCLC转移中的有效性。 2）使用基因设计的自化kras驱动的肺癌小鼠模型以及药物抑制或遗传灭活ABL激酶，定义了ABL家族激酶在肺部肿瘤进展中的作用。 3）评估对ABL激酶的抑制是否会感受到选择的治疗 - 不良肿瘤对靶向化学疗法的生长抑制，并剖析该反应的基础机制。该提案的结果将产生对选定中ABL激酶调节的信号网络的新见解 肺癌细胞。此外，新的特异性ABL激酶抑制剂以及鼠标的可用性 在我们实验室中产生的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治疗 - 难治性肺癌的靶标。