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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肺癌是美国癌症相关死亡的主要原因，并且对人类的影响尤为严重退伍军人。过去十年非小细胞肺癌的进展带来了新的治疗方法分子靶向治疗具有最小的毒性作用和显着的临床益处。然而，尽管取得了这些进展，总体五年生存率仍保持在 16% 左右，部分原因是低对靶向治疗的反应率、获得性耐药的发展、靶向某些药物的困难蛋白质，例如突变的 K-RAS，以及具有未定义的遗传改变的大子集。所以，目前难以利用的肺癌亚型需要新的分子靶点治疗。 EphA2 就是一个很有前景的靶点。 EphA2 在 NSCLC 中过表达，并且 EphA2 水平高与吸烟、脑转移、疾病复发和患者生存率低相关。增益- 功能 EphA2 突变也在肿瘤标本中被发现，表明其具有致癌作用 EphA2 在肺癌中的作用。事实上，我们发现大量的 EphA2 基因被敲低。人肺癌细胞系抑制肿瘤细胞活力，对那些携带者的影响最为显着突变 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，EphA2 小分子激酶抑制剂抑制了细胞 K-RAS 突变人肺癌异种移植物的体外活力和诱导肿瘤消退。基于根据这些初步数据，本次 VA 功绩更新的总体目标是确定针对当前靶向治疗难治的肺癌亚型中的 EphA2，以阐明 EphA2 在肿瘤中发挥作用的分子基础，并测试小分子 EphA2 激酶抑制剂癌症治疗。我们将首先研究 EphA2 缺陷对肺癌发生和发展的影响。转基因 K-RAS G12D 和 TKI 耐药 EGFR L858R+T790M 肺癌模型中的体内进展。到阐明EphA2受体下游信号传导，我们将重点关注JNK/c-Jun通路在调节中的作用肿瘤细胞活力和肿瘤干样细胞功能。最后，我们将测试选择性小样本的功效 EphA2受体分子抑制剂。该项目的成功不仅会产生新的见解 EphA2 RTK 调节肿瘤细胞活力的分子基础，同时也提供了新的 EphA2- 用于治疗目前靶向药物难以治疗的肺癌亚型的选择性抑制剂治疗，例如 K-RAS 突变和耐药 EGFR 突变肺癌。