EphA2 kinase in prostate cancer

描述（由申请人提供）：本提案有两个主要目标。一是阐明Akt-EphA2信号轴是否是人类前列腺癌（PCa）恶性进展的“驱动”机制；二是评价epha2靶向小分子对PCa的治疗效果。大约70%的原发性前列腺癌表现出至少一个PTEN等位基因的缺失，两个等位基因的缺失与晚期疾病有关。PTEN缺失导致PI3K/Akt活化。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可能通过共选择EphA2激酶促进肿瘤细胞的迁移和侵袭。EphA2在癌症中被广泛研究。它在许多不同类型的人类癌症中经常过表达，这通常与肿瘤进展有关。虽然这些数据表明EphA2是一种致癌基因，但也有强有力的证据表明EphA2具有肿瘤抑制功能。为了阐明这一明显的悖论，我们最近报道了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的配体存在下，EphA2抑制细胞迁移和侵袭。相反，在没有配体的情况下，EphA2反而促进趋化迁移和侵袭。有趣的是，与配体无关的细胞运动刺激与Akt在单个丝氨酸残基（S897）上磷酸化EphA2相关。S897A突变消除了这种与配体无关的效应。初步研究表明，PTEN缺失诱导的高级别人PCa和小鼠PCa侵袭前检测到S897磷酸化，提示Akt-EphA2信号轴在PCa中存在病理相关性。综合这些数据，我们推测Akt-EphA2串扰有助于前列腺癌的侵袭和转移，可以作为前列腺癌治疗的靶点。提出了三个目标。我们将验证Akt-EphA2信号轴是促进人类PCa恶性进展的“驱动”机制。在Aim 2中，我们将确定ephrin-As能否排斥传播的PCa细胞。目的3将研究以EphA2为靶点的小分子能否在体内作为抑制前列腺癌转移的潜在治疗药物。

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.