Prostate Cancer: Transition to Androgen - Independence (CA77739)

正在进行的这一POI研究对雄激素受体(AR)信号在雄激素剥夺过程中前列腺癌(CAP)复发至关重要的概念做出了重大贡献。首先，人们发现，复发帽中的组织雄激素水平足以刺激AR的生长，而阻断AR功能会抑制生长。这些观察结果得到了最近的临床试验的很好的支持，这些试验表明，复发性CAP对类固醇生成酶抑制剂的治疗有很好的反应，这种抑制剂可以阻止CAP组织中雄激素的合成。其次，随着MAGE-11的发现，在理解AR刺激细胞增殖方面取得了重大进展。MAGE-11是一种AR辅助调节因子，在复发性CAP中过度表达，通过与关键的细胞周期调节蛋白和肿瘤抑制因子相互作用，将AR与细胞生长联系起来。初步研究表明MAGE-11在AR刺激细胞增殖中起着至关重要的作用。第三，AR存在于前列腺微血管内皮细胞中。一种独特的人前列腺异种移植模型已经被开发出来，该模型利用根治性前列腺切除标本的新鲜组织，允许研究AR在前列腺微血管中的作用，以及雄激素跨内皮屏障的运输调节。这一POI应用的统一假设是，通过雄激素剥夺治疗结合针对AR的新策略可以更有效地治疗晚期CAP。项目1将在去势后使用阻止雄激素合成、导致AR配体或其前体降解和/或消除AR功能的策略来消除OFAR转录活性。项目2将MAGE-11描述为抑制AR刺激的细胞生长的靶点。它将建立MAGE-11表达的细胞周期依赖性和MAGE-11基因敲除对细胞增殖的影响，鉴定MAGE-11失活视网膜母细胞瘤口袋蛋白Rb和p107的腺病毒EIA样特性，并确定MAGE-11和Rb/p107通过降解p27-Kip1肿瘤抑制因子对Skp2刺激细胞增殖的影响。项目3将确定雄激素剥夺对前列腺微血管内皮细胞功能的影响，包括雄激素内吞、代谢和运输，确定HNF-4a在CAP干细胞中的异常功能，并在雄激素剥夺治疗期间使用与扰乱内皮类固醇屏障相关的策略靶向CAP干细胞。

Ongoing research in this POI has contributed significantly to the concept that androgen receptor (AR) signaling is essential to the recurrence of prostate cancer (CaP) during androgen deprivation. First, it was discovered that tissue androgen levels in recurrent CaP are sufficient for AR stimulation of growth, and that blocking AR function inhibits growth. These observations are well supported by recent clinical trials showing that recurrent CaP responds to treatment with a steroidogenic enzyme inhibitor that blocks the synthesis of androgens in CaP tissue. Second, with the discovery of MAGE-11, major progress has been made towards understanding AR stimulation of cell proliferation. MAGE-11, an AR coregulator overexpressed in recurrent CaP, links AR to cell growth through interactions with key cell cycle regulatory proteins and tumor suppressors. Initial studies indicate that MAGE-11 is vital to AR stimulation of cell proliferation. Third, AR was identified in endothelial cells of the prostate microvasculature. A unique human prostate xenograft model that utilizes fresh tissue from radical prostatectomy specimens has been developed that allows for the study of AR action in the prostate microvasculature, and the regulation of androgen transport across the endothelial barrier. The unifying hypothesis of this POI application is that advanced CaP can be treated more effectively by androgen deprivation therapy combined with new strategies that target the AR. Project 1 will pursue the elimination ofAR transcriptional activity during the post-castration period using strategies that prevent the synthesis of androgen, cause the degradation of AR ligands or their precursors and/or eliminate AR function. Project 2 will characterize MAGE-11 as a target for inhibition of AR-stimulated cell growth. It will establish the cell cycle dependence of MAGE-11 expression and the effect of MAGE-11 knockdown on cell proliferation, identify the adenovirus EIA-Iike properties of MAGE-11 that inactivate the retinoblastoma pocket proteins, Rb and p107, and determine the influence of MAGE-11 and Rb/p107 on Skp2 stimulation of cell proliferation through the degradation of the p27-Kip1 tumor suppressor. Project 3 will determine the effects of androgen deprivation on endothelial cell functions ofthe prostate microvasculature including androgen endocytosis, metabolism and transport, identify aberrant functions of HNF-4a in CaP stem cells, and target CaP stem cells using strategies related to perturbation of the endothelial steroid barrier during androgen deprivation therapy.