Targeting EphA2 in lung cancer subtypes that are refractory to current therapy

针对当前治疗难治的肺癌亚型中的 EphA2

• 批准号: 8627397
• 负责人: Jin Chen
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627397
• 关键词: Affect; Animal Model; Antibodies; Apoptosis; Arts; Biochemical; Biology; Cancer Biology; Cancer Etiology; Cancer Model; Cancer cell line; Categories; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cell physiology; Cell surface; Cells; Cessation of life; Chemicals; Clinical; Collaborations; Data; Development; Disease; Drug Targeting; Drug resistance; Eph Family Receptors; EphA2 Receptor; Epidermal Growth Factor Receptor; Exhibits; Gatekeeping; Goals; Gray unit of radiation dose; Half-Life; Human; Image; In Situ; In Vitro; Incidence; Investigation; JUN gene; Lead; Lesion; Luciferases; MAP Kinase Gene; MAPK8 gene; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Medicine; Metastatic malignant neoplasm to brain; Molecular; Molecular Target; Monitor; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Pathway interactions; Patients; Pharmaceutical Chemistry; Phosphorylation; Phosphotransferases; Population; Proteins; Proteomics; Recurrent disease; Refractory; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Smoking; Specificity; Specimen; Survival Rate; Technology; Testing; Therapeutic; Time; Toxic effect; Transgenic Organisms; Tyrosine Kinase Inhibitor; United States; Veterans; Xenograft procedure; abstracting; anticancer research; base; cancer cell; cell behavior; cell growth; efficacy testing; gain of function; genome-wide; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; insight; kinase inhibitor; lung development; mouse model; multidisciplinary; mutant; neoplastic cell; novel; overexpression; public health relevance; response; rho; screening; small molecule; src-Family Kinases; stem; success; therapeutic target; therapy development; tumor; tumor growth

Project Summary/ Abstract Lung cancer is the leading cause of cancer-related deaths in the US and disproportionally affects Veterans. Advances in non-small-cell lung cancer over the past decade have resulted in new molecularly targeted therapies with minimal toxic effects and dramatic clinical benefits. However, despite these progresses, overall five-year survival remains at approximately 16%, partly due to low responsive rate to targeted therapy, development of acquired resistance, difficulty of targeting certain proteins such as mutant K-RAS, and a large subset with undefined genetic alterations. Therefore, new molecular targets are needed for lung cancer subtypes that are currently refractory to available treatments. EphA2 is such a promising target. EphA2 is overexpressed in NSCLC, and high levels of EphA2 correlate with smoking, brain metastasis, disease relapse, and poor patient survival. A gain-of- function EphA2 mutation has also been identified in tumor specimens, suggesting an oncogenic role of EphA2 in lung cancer. Indeed, we discovered that knockdown of EphA2 in a large numbers of human lung cancer cell lines inhibited tumor cell viability, most dramatically affecting those bearing mutant K-RAS or carrying EGFR mutation that developed acquired resistance to tyrosine kinase inhibitors (TKI). To support this notion, an EphA2 small molecule kinase inhibitor suppressed cell viability in vitro and induced tumor regression in K-RAS mutant human lung cancer xenografts. Based on these preliminary data, the overall goal of this VA Merit renewal is to determine the efficacy of targeting EphA2 in lung cancer subtypes that are refractory to current targeted treatment, to elucidate molecular basis for EphA2 function in tumor, and to test small molecule EphA2 kinase inhibitors for cancer therapeutics. We will first to investigate the effects of EphA2 deficiency on lung cancer development and progression in vivo in transgenic K-RAS G12D and TKI-resistant EGFR L858R+T790M lung cancer models. To elucidate EphA2 receptor downstream signaling, we will focus on the JNK/c-Jun pathway in regulating tumor cell viability and tumor stem-like cell function. Finally, we will test the efficacy of selective small molecule inhibitors of EphA2 receptor. Success of this project will not only generate novel insights into the molecular basis whereby EphA2 RTK regulates tumor cell viability, but also provide novel EphA2- selective inhibitors for treatment of lung cancer subtypes that are refractory to current targeted therapies, such as K-RAS mutant and drug-resistant EGFR mutant lung cancers.

项目总结/摘要 肺癌是美国癌症相关死亡的主要原因， 老兵在过去的十年中，非小细胞肺癌的进展导致了新的 具有最小毒性作用和显著临床益处的分子靶向疗法。然而，在这方面， 尽管取得了这些进展，但总体5年生存率仍约为16%，部分原因是低 对靶向治疗的反应率，获得性耐药性的发展，靶向某些 蛋白质，如突变K-RAS，和一个大的子集与未定义的遗传改变。因此，我们认为， 对于目前难治的肺癌亚型，需要新的分子靶点。 治疗。 EphA 2是一个很有前途的目标。EphA 2在NSCLC中过表达，高水平的EphA 2 与吸烟、脑转移、疾病复发和患者生存率差相关。一个增益- 在肿瘤标本中也发现了EphA 2功能突变，提示其致癌作用 EphA 2在肺癌中的作用事实上，我们发现，在大量的细胞中EphA 2的敲除， 人肺癌细胞系抑制肿瘤细胞活力，对携带肿瘤细胞的影响最为显着 突变型K-RAS或携带EGFR突变，对酪氨酸激酶产生获得性耐药 抑制剂（TKI）。为了支持这一观点，EphA 2小分子激酶抑制剂抑制了细胞增殖。 K-RAS突变人肺癌异种移植物中的体外存活力和诱导的肿瘤消退。基于 根据这些初步数据，此次VA Merit更新的总体目标是确定 靶向目前靶向治疗难治的肺癌亚型中的EphA 2，以阐明 EphA 2在肿瘤中的功能的分子基础，并测试小分子EphA 2激酶抑制剂， 癌症治疗学 我们将首先研究EphA 2缺乏对肺癌发展的影响， 在转基因K-RAS G12 D和TKI耐药EGFR L 858 R + T790 M肺癌模型中的体内进展。到 为了阐明EphA 2受体下游信号传导，我们将重点关注JNK/c-Jun通路在调节EphA 2受体下游信号传导中的作用。 肿瘤细胞活力和肿瘤干细胞样细胞功能。最后，我们将测试选择性小 EphA 2受体的分子抑制剂。这个项目的成功不仅会产生新的见解， EphA 2 RTK调节肿瘤细胞活力的分子基础，但也提供了新的EphA 2- 用于治疗目前靶向治疗难治的肺癌亚型的选择性抑制剂 治疗，如K-RAS突变和耐药EGFR突变肺癌。