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

描述（由申请人提供）：前列腺癌是美国男性死亡的第二大原因。睾酮(T)或双氢睾酮（DHT）激活的雄激素受体（AR）在前列腺癌的所有阶段都起着关键作用。去势去除循环T，使前列腺癌细胞失去T和DHT，是有症状的高风险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），这是不可治愈的，通常是致命的。即使在阉割后，AR信号仍然是疾病进展的主要驱动力。CRPC能够通过使用胆固醇或循环肾上腺雄激素脱氢表雄酮（DHEA）和硫酸脱氢表雄酮（DHEAS）的内分泌雄激素代谢产生T或DHT。去势不显著降低循环脱氢表雄酮和脱氢表雄酮。脱氢表雄酮（DHEAS）的血清浓度比脱氢表雄酮（DHEA）高100 ~ 400倍。DHEAS比胆固醇更接近最终产物，为T或DHT的合成提供了更节能的底物。此外，脱氢表雄酮在血清中的半衰期比脱氢表雄酮长。因此，DHEAS为CRPC细胞分泌T或DHT提供了一个潜在的前体来源。然而，DHEAS很少受到关注。DHEAS是如何被前列腺癌细胞获取和利用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）是脱氢表雄酮（DHEAS）水解为脱氢表雄酮（DHEA）生成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）的调控。该研究的中心假设是，剥夺前列腺癌细胞的DHEAS将改善对去势的反应，并防止CRPC的进展。中心假设将在三个具体目标中进行检验。目的1通过对一组组织微阵列切片的免疫组织化学处理，探讨STS、IGF1R和IR在CRPC中的临床相关性。目的2通过体内模型和抑制STS和IGF1R/IR来评估前列腺癌细胞靶向DHEAS用于阻止去势后肿瘤生长的价值。目的3确定最有效的DHEAS摄取转运蛋白，并测试使用细胞模型筛选DHEAS转运蛋白阻滞剂的可行性。提出的研究需要验证DHEAS是前列腺癌细胞分泌T和DHT的重要前体来源的概念。这些研究结果将为如何阻断前列腺癌细胞对DHEAS的使用提供新的见解，从而通过靶向DHEAS转运体、STS和STS调节因子，促进更完整的雄激素剥夺治疗。

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.