EphA2 kinase in prostate cancer

描述（由申请人提供）：本提案有两个主要目标。一个是阐明Akt-EphA 2信号传导轴是否是人类前列腺癌（PCa）恶性进展的“驱动”机制;另一个是评估EphA 2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等位基因的丢失，并且两个等位基因的丢失与晚期疾病相关。PTEN缺失导致PI 3 K/Akt的激活。虽然Akt控制细胞增殖和存活是众所周知的，但它如何调节肿瘤进展尚不清楚。我们发现Akt可能通过协同EphA 2激酶促进肿瘤细胞的迁移和侵袭。EphA 2在癌症中被广泛研究。它经常在许多不同类型的人类癌症中过表达，这通常与肿瘤进展相关。虽然这些数据表明EphA 2是一种致癌基因，但也存在强有力的证据证明EphA 2的肿瘤抑制功能。为了阐明这一明显的矛盾，我们最近报道了EphA 2在调节PCa细胞迁移和侵袭中具有完全相反的作用。在称为ephrin-As的配体存在下，EphA 2抑制细胞迁移和侵袭。相反，在配体不存在的情况下，EphA 2反而促进趋化性迁移和侵袭。有趣的是，配体非依赖性的细胞运动性刺激与Akt对EphA 2在单个丝氨酸残基（S897）上的磷酸化相关。S897 A突变消除了这种配体非依赖性效应。初步研究表明，在高级别人PCa和由PTEN缺失诱导的小鼠PCa的侵袭前沿检测到S897磷酸化，表明Akt-EphA 2信号传导轴在PCa中的病理相关性。总的来说，这些数据使我们假设Akt-EphA 2串扰有助于PCa的侵袭和转移，并且可以被靶向用于PCa治疗。提出了三个目标。目的是验证Akt-EphA 2信号轴是促进人前列腺癌恶性进展的“驱动”机制的假设。目的2：确定ephrin-As对PCa细胞的排斥作用。目的3将研究靶向EphA 2的小分子是否可以用作潜在的治疗剂来抑制体内PCa转移。

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.