Deprive prostate cancer of DHEAS to prevent castration-recurrent prostate cancer

描述(申请人提供)：前列腺癌是美国男性的第二大死因。睾酮(T)或双氢睾酮(DHT)激活的雄激素受体(AR)在前列腺癌的各个阶段都起着关键作用。去势可以去除循环中的T，使前列腺癌细胞中的T和DHT减少，是有症状的高危局部晚期或转移性前列腺癌的首选治疗方法。去势治疗的前列腺癌最初反应良好，但不可避免地发展为去势复发性前列腺癌(CRPC)，这种癌症是无法治愈的，通常是致命的。AR信号仍然是疾病进展的主要驱动力，即使在去势之后。CRPC能够通过使用胆固醇或循环中的肾上腺雄激素脱氢表雄酮(DHEA)和DHEA硫酸盐(DHEAS)的内分泌雄激素代谢产生T或DHT。去势不会显著减少循环中的脱氢表雄酮和脱氢表雄酮。脱氢表雄酮的血清浓度是脱氢表雄酮的400倍。DHEAS比胆固醇更接近最终产品，为合成T或DHT提供了更节能的底物。此外，DHEAS在血清中的半衰期比DHEA长。因此，DHEAS为CRPC细胞分泌大量的T或DHT提供了潜在的前体来源。然而，DHEAS几乎没有受到关注。前列腺癌细胞如何获得和使用DHEAS的问题是至关重要的。前列腺癌细胞对DHEAS的摄取可能是由一类特殊的跨膜转运蛋白介导的。类固醇硫酸酯酶(STS)是将DHEAS分解为DHEA以产生T和DHT所必需的酶，可能受胰岛素受体(IR)和胰岛素样生长因子1受体(IGF1R)的调节。这项拟议研究的中心假设是，剥夺前列腺癌细胞中的DHEAS将改善对去势的反应，并防止进展为CRPC。核心假设将在3个具体目标中得到检验。目的1应用免疫组织化学方法对一组组织芯片切片进行研究，探讨STS、IGF1R和IR在CRPC中的临床意义。目的2通过体内模型评价前列腺癌细胞靶向使用DHEAS预防去势后肿瘤生长的价值以及抑制STS和IGF1R/IR的作用。目的3确定最有效的DHEAS摄取转运体，并测试使用细胞模型筛选DHEAS转运体阻滞剂的可行性。建议的研究需要验证DHEAS是前列腺癌细胞分泌T和DHT的重要前体来源这一概念。这些研究的结果将为如何通过靶向DHEAS转运体、STS和STS调节器来阻止前列腺癌细胞使用DHEAS来促进更全面的雄激素剥夺治疗提供洞察力。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of death in men in the US. Testosterone (T) - or dihydrotestosterone (DHT) -activated androgen receptor (AR) plays a critical role in prostate cancer during all stages. Castration removes circulating T t deprive prostate cancer cells of T and DHT, and is the preferred treatment for symptomatic high-risk locally advanced or metastatic prostate cancer. Castration-treated prostate cancer initially responds well, but inevitably progresses to castration-recurrent prostate cancer (CRPC), which is incurable and usually fatal. AR signaling remains a predominant driving force for disease progression even after castration. CRPC are able to produce T or DHT through intracrine androgen metabolism that uses cholesterol or circulating adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Castration does not significantly reduce circulating DHEA and DHEAS. Serum concentrations of DHEAS are >400-fold higher than those of DHEA. DHEAS is much closer to the final products than cholesterol to provide a more energy-efficient substrate for synthesis of T or DHT. Also, DHEAS has a longer half-life in the serum than DHEA. Therefore, DHEAS presents a potential source of precursor that is highly abundant for intracrine production of T or DHT by CRPC cells. However, DHEAS has received little attention. The question of how DHEAS is made available to and used by prostate cancer cells is critically important. The uptake of DHEAS by prostate cancer cells may be mediated by a special class of transmembrane transporters. Steroid sulfatase (STS) is required to hydrolyze DHEAS to DHEA for T and DHT production, and may be regulated by insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R). The central hypothesis of the proposed research is that depriving prostate cancer cells of DHEAS will improve response to castration and prevent the progression to CRPC. The central hypothesis will be tested in 3 specific aims. Aim 1 addresses clinical relevance of STS, IGF1R, and IR in CRPC using immunohistochemistry on sections of a set of tissue microarrays. Aim 2 evaluates the value of targeting DHEAS usage by prostate cancer cells to prevent post-castration tumor growth using in vivo models and inhibition of STS and IGF1R/IR. Aim 3 identifies the most potent DHEAS uptake transporters and tests the feasibility of using a cell model to screen for DHEAS transporter blockers. The proposed studies are required to validate the concept that DHEAS is an important source of precursors for intracrine production of T and DHT by prostate cancer cells. Findings from the studies will provide insight into how to block the use of DHEAS by prostate cancer cells to facilitate more complete androgen deprivation therapy by targeting DHEAS transporters, STS, and STS regulators.