Prostate Cancer: Transition to Androgen - Independence (CA77739)

目前正在进行的研究在这个POI的概念，雄激素受体（AR）信号是必不可少的前列腺癌（CaP）在雄激素剥夺复发作出了重大贡献。首先，发现复发性CaP中的组织雄激素水平足以刺激AR生长，并且阻断AR功能抑制生长。最近的临床试验充分支持了这些观察结果，这些临床试验表明，复发性CaP对用类固醇生成酶抑制剂治疗有反应，该抑制剂阻断CaP组织中雄激素的合成。其次，随着法师-11的发现，在理解AR刺激细胞增殖方面取得了重大进展。法师-11是一种在复发性CaP中过表达的AR辅助调节因子，通过与关键细胞周期调节蛋白和肿瘤抑制因子的相互作用将AR与细胞生长联系起来。初步研究表明，法师-11是至关重要的AR刺激细胞增殖。第三，在前列腺微血管内皮细胞中鉴定出AR。已经开发了利用来自根治性前列腺切除术标本的新鲜组织的独特的人前列腺异种移植物模型，其允许研究前列腺微血管中的AR作用，以及雄激素转运穿过内皮屏障的调节。该POI应用的统一假设是，晚期CaP可以通过雄激素剥夺疗法结合靶向AR的新策略来更有效地治疗。项目1将采用阻止雄激素合成、导致AR配体或其前体降解和/或消除AR功能的策略，在去势后期间消除AR转录活性。项目2将表征法师-11作为抑制AR刺激的细胞生长的靶标。它将建立法师-11表达的细胞周期依赖性和法师-11敲低对细胞增殖的影响，鉴定法师-11的腺病毒EIA样性质，其抑制视网膜母细胞瘤口袋蛋白Rb和p107，并确定法师-11和Rb/p107通过降解p27-Kip 1肿瘤抑制因子对Skp 2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、代谢和转运，确定CaP干细胞中HNF-4a的异常功能，并使用与雄激素剥夺治疗期间内皮类固醇屏障扰动相关的策略靶向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.