EphA2 kinase in prostate cancer

前列腺癌中的 EphA2 激酶

基本信息

批准号：
8034022
负责人：
Bingcheng Wang
金额：
$ 32.58万
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/8034022
关键词：
Address Affect Agonist Alleles Androgens Benign Breeding Cancer Biology Cancer Patient Castration 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 Resistance 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 cancer cell cell motility falls in vivo innovation member men migration novel novel therapeutics overexpression pre-clinical small molecule therapy development treatment strategy tumor 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. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the most prevalent type of tumors in the US men with an estimated 186,320 new cases and 28,660 deaths in 2009. At the time of diagnosis, prostate cancer (PCa) patients generally fall into one of two groups. For most PCa patients, the disease is benign. However, in a minority of patients, the disease undergoes rapid malignant progression leading to metastasis with bones as the most frequently affected site. Although the majority of men with metastatic prostate cancer will initially respond to androgen depletion therapy, the development of castration-resistant PCa almost always occurs, accompanied by further metastatic progression. Integral to tumor metastasis is the acquisition of migratory and invasive phenotype. The central goal of this proposal is to investigate the newly characterized Akt-EphA2 crosstalk as a novel "on and off switch" in controlling PCa cell migration, and whether it can targeted for therapy of malignant PCa. Completion of the proposed studies will not only lead to better understanding of prostate cancer biology, but also potentially novel therapeutic agents treatment strategies for the more malignant subgroup of the disease.

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。公共卫生相关性：前列腺癌（PCA）是美国男性最普遍的肿瘤类型，估计为186,320例新病例，在2009年死亡28,660例。在诊断时，前列腺癌（PCA）患者通常属于两组之一。对于大多数PCA患者，该疾病是良性的。但是，在少数患者中，该疾病经历了快速的恶性进展，导致骨骼转移是最常见的部位。尽管大多数转移性前列腺癌的男性最初会对雄激素耗尽疗法做出反应，但持续性PCA的发展几乎总是发生，并伴随着进一步的转移进展。肿瘤转移的积分是迁移和侵入性表型的获取。该提案的核心目的是研究在控制PCA细胞迁移时，将新近特征的Akt-Epha2串扰作为一种新颖的“开关开关”，以及它是否可以针对恶性PCA治疗。拟议的研究的完成不仅会更好地理解前列腺癌生物学，而且还将为该疾病的更恶性亚群提供潜在的新型治疗剂治疗策略。