EphA2 kinase in prostate cancer

描述(由申请人提供)：这项提案有两个主要目标。一是阐明Akt-EphA2信号轴是否是前列腺癌恶性进展的驱动机制；二是评价EphA2靶向小分子对前列腺癌的治疗效果。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都与晚期疾病有关。PTEN缺失导致PI3K/Akt激活。虽然Akt控制细胞增殖和存活是众所周知的，但它如何调控肿瘤进展还不是很清楚。我们发现Akt可能通过共激活EphA2激酶来促进肿瘤细胞的迁移和侵袭。EphA2在癌症中得到了广泛的研究。它经常在许多不同类型的人类癌症中过度表达，这通常与肿瘤的进展有关。虽然这些数据表明EphA2是一个癌基因，但也有强有力的证据表明EphA2具有肿瘤抑制功能。为了揭示这一明显的悖论，我们最近报道了EphA2在调控PCa细胞迁移和侵袭方面具有截然相反的作用。在Ephin-AS配体的存在下，EphA2抑制了细胞的迁移和侵袭。相反，在缺乏配体的情况下，EphA2反而促进了趋化迁移和侵袭。有趣的是，对细胞运动的非配体依赖的刺激与Akt对单个丝氨酸残基(S897)上的EphA2的磷酸化有关。S897A突变取消了这种配体非依赖的效应。初步研究表明，PTEN缺失诱导的人和小鼠PCa的侵袭性前沿有S897的磷酸化，提示Akt-EphA2信号轴与PCa的病理相关。总而言之，这些数据使我们假设Akt-EphA2串扰有助于PCa的侵袭和转移，并可作为PCa治疗的靶点。提出了三个目标。目的验证Akt-EphA2信号轴是促进人前列腺癌恶性进展的驱动机制的假说。在目标2中，我们将确定ePhin-AS可以阻止PCa细胞的扩散。目的3探讨靶向EphA2的小分子药物能否作为体内抑制前列腺癌转移的潜在治疗药物。 与公共卫生相关：前列腺癌(PCA)是美国男性最常见的肿瘤类型，2009年估计有186,320例新病例和28,660例死亡。确诊时，前列腺癌(PCA)患者通常分为两组。对于大多数前列腺癌患者来说，这种疾病是良性的。然而，在少数患者中，疾病经历了快速的恶性进展，导致转移，骨骼是最常见的受累部位。虽然大多数转移性前列腺癌患者最初会对雄激素耗竭治疗有反应，但几乎总是会发生去势抵抗的前列腺癌的发展，伴随着进一步的转移进展。肿瘤转移的关键是获得移行和侵袭表型。该方案的中心目标是研究Akt-EphA2串扰作为控制PCa细胞迁移的一种新的“开关”，以及它是否可以靶向治疗恶性PCa。拟议研究的完成不仅将使人们更好地了解前列腺癌的生物学，而且还可能为恶性程度更高的疾病亚组提供新的治疗药物治疗策略。

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.