EphA2 kinase in prostate cancer

前列腺癌中的 EphA2 激酶

基本信息

批准号：
8544181
负责人：
Bingcheng Wang
金额：
$ 30.62万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8544181
关键词：
Address Affect Agonist Alleles Androgens Benign Breeding Cancer Biology Cancer Patient Cell Migration Inhibition function Cell Proliferation Cell Survival Cells Cessation of life Clinical Complex Data Diagnosis Disease Distal EphA2 Receptor Ephrin-A1 Ephrins Exhibits Genes Gleason Grade for Prostate Cancer Goals Growth Human In Vitro Knock-out Knockout Mice Lead Ligand Binding Domain Ligands Light Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Minority Mus Mutation Neoplasm Metastasis Oncogenes PTEN gene Patients Pharmaceutical Chemistry Phenotype Phosphorylation Phosphotransferases Prostate Cancer therapy Reporting Role Serine Signal Transduction Site Specimen Staining method Stains Structure Subgroup Testing Therapeutic Agents Time Treatment Efficacy Tumor Cell Invasion Tumor Suppressor Proteins Xenograft Model Xenograft procedure advanced disease base bone castration resistant prostate cancer cell motility falls in vivo innovation member men migration novel novel therapeutics overexpression pre-clinical prostate cancer cell small molecule therapy development treatment strategy tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): There are two major goals in this proposal. One is to elucidate if Akt-EphA2 signaling axis is a "driver" mechanism underlying malignant progression of human prostate cancer (PCa); the other is to evaluate therapeutic efficacy of EphA2-targeted small molecules against PCa. Approximately 70% of primary PCa exhibit a loss of at least one PTEN allele and loss of both alleles is associated with advanced disease. PTEN loss leads to activation of PI3K/Akt. While Akt is well-known to control cell proliferation and survival, how it may regulate tumor progression is not well understood. We discovered that Akt may promote tumor cell migration and invasion by co-opting EphA2 kinase. EphA2 has been extensively studied in cancer. It is frequently overexpressed in many different types of human cancer, which is often correlated with tumor progression. While these data suggest EphA2 is an oncogene, strong evidence also exists demonstrating tumor suppressor functions of EphA2. Shedding light on this apparent paradox, we reported recently that EphA2 has diametrically opposite roles in regulating PCa cell migration and invasion. In the presence of ligands called ephrin-As, EphA2 inhibited cell migration and invasion. In contrast, in the absence of ligands EphA2 promoted chemotactic migration and invasion instead. Interestingly the ligand-independent stimulation of cell motility was correlated with phosphorylation of EphA2 on a single serine residue (S897) by Akt. S897A mutation abolished this ligand-independent effect. Preliminary studies show that S897 phosphorylation is detected at invasive front of high grade human PCa and mouse PCa induced by PTEN deletion, suggesting pathological relevance of Akt-EphA2 signaling axis in PCa. The data in aggregate led us to hypothesize that the Akt-EphA2 crosstalk contributes to invasion and metastasis of PCa and can be targeted for PCa therapy. Three aims are proposed. Aim will test the hypothesis that Akt-EphA2 signaling axis is a "driver" mechanism in promoting malignant progression of human PCa. In Aim 2, we will determine ephrin-As can repulse disseminating PCa cells. Aim 3 will investigate whether small molecule targeting EphA2 can be used as potential therapeutic agents to suppress PCa metastasis in vivo.

描述（由申请人提供）：该提案中有两个主要目标。一种是阐明AKT-EPHA2信号轴是否是人类前列腺癌恶性进展的“驱动器”机制（PCA）；另一个是评估EPHA2靶向小分子对PCA的治疗功效。大约70％的原发性PCA表现出至少一个PTEN等位基因，并且两个等位基因的损失与晚期疾病有关。 PTEN损失导致PI3K/AKT的激活。尽管AKT众所周知，可以控制细胞的增殖和存活，但它如何调节肿瘤进展并未得到充分了解。我们发现AKT可以通过选择EPHA2激酶来促进肿瘤细胞迁移和侵袭。 EPHA2已在癌症中进行了广泛的研究。它在许多不同类型的人类癌症中经常过表达，这通常与肿瘤进展相关。尽管这些数据表明epha2是一种癌基因，但也存在有力的证据，证明了EPHA2的肿瘤抑制功能。阐明了这一明显的悖论，我们最近报道说，以Epha2在调节PCA细胞迁移和侵袭中具有截然相反的作用。在称为ephrin-as的配体的存在下，以etpha2抑制了细胞迁移和侵袭。相反，在没有配体的情况下，epha2促进了趋化性迁移和侵袭。有趣的是，AKT在单个丝氨酸残基（S897）上，与配体无关的细胞运动刺激与EPHA2的磷酸化相关。 S897a突变消除了这种与配体无关的作用。初步研究表明，在PTEN缺失诱导的高级人PCA和小鼠PCA的侵入性前沿检测到S897磷酸化，这表明PCA中AKT-EPHA2信号轴的病理相关性。总体数据使我们假设Akt-Epha2串扰有助于PCA的侵袭和转移，并且可以针对PCA治疗。提出了三个目标。 AIM将检验以下假设：AKT-EPHA2信号轴是促进人PCA恶性进展的“驱动器”机制。在AIM 2中，我们将确定ephrin-as可以排斥传播PCA细胞。 AIM 3将研究靶向EPHA2的小分子是否可以用作抑制体内PCA转移的潜在治疗剂。