权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

剥夺前列腺癌中的 DHEAS 以预防去势复发性前列腺癌

基本信息

批准号：
8928591
负责人：
Yue Wu
金额：
$ 22.9万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-17 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928591
关键词：
Address Adrenal Glands Androgen Metabolism Androgen Receptor Androgens Attention Benign Blood Circulation Cancer Patient Castration Cause of Death Cell model Cholesterol Dehydroepiandrosterone Sulfate Disease Disease Progression Goals Growth Half-Life Health Human Immunohistochemistry In Vitro Insulin Insulin Receptor Insulin-Like-Growth Factor I Receptor Knowledge Life Malignant neoplasm of prostate Mediating Membrane Metastatic Prostate Cancer Mission Modality Modeling Patients Play Pre-Clinical Model Process Production Prostate Prostatic Tissue Proteins Public Health Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Research Role Serum Source Specimen Staging Stanolone Steryl-sulfatase Supplementation Testing Testosterone Therapeutic Tissue Microarray Tissues Xenograft Model cancer therapy clinically relevant dehydroepiandrosterone deprivation driving force efficacy testing experience high risk improved in vivo in vivo Model inhibitor/antagonist insight men mouse model novel therapeutic intervention prevent prostate cancer cell prostate cancer cell line prototype response sulfate transporter targeted treatment tumor growth uptake

项目摘要

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.

描述（由申请人提供）：前列腺癌是美国男性的第二大死因。睾酮 (T) 或二氢睾酮 (DHT) 激活的雄激素受体 (AR) 在前列腺癌的各个阶段都发挥着关键作用。去势可去除循环 T t 剥夺前列腺癌细胞的 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，但不可避免地会发展为去势复发性前列腺癌（CRPC），这是无法治愈的，通常是致命的。即使在去势后，AR 信号传导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 DHEA (DHEAS) 的内分泌雄激素代谢产生 T 或 DHT。去势不会显着减少循环中的 DHEA 和 DHEAS。 DHEAS 的血清浓度比 DHEA 高 400 倍以上。 DHEAS 比胆固醇更接近最终产品，为 T 或 DHT 的合成提供更节能的底物。此外，DHEAS 在血清中的半衰期比 DHEA 更长。因此，DHEAS 是 CRPC 细胞内分泌 T 或 DHT 的高度丰富的前体来源。然而，DHEAS 却很少受到关注。前列腺癌细胞如何利用 DHEAS 的问题至关重要。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) 将 DHEAS 水解为 DHEA，以产生 T 和 DHT，并且可能受到胰岛素受体 (IR) 和胰岛素样生长因子 1 受体 (IGF1R) 的调节。这项研究的中心假设是，剥夺前列腺癌细胞的 DHEAS 将改善对去势的反应并防止进展为 CRPC。中心假设将在 3 个具体目标中进行检验。目标 1 使用免疫组织化学对一组组织微阵列切片探讨 STS、IGF1R 和 IR 在 CRPC 中的临床相关性。目标 2 使用体内模型以及抑制 STS 和 IGF1R/IR 来评估前列腺癌细胞使用 DHEAS 来预防去势后肿瘤生长的价值。目标 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 转运蛋白阻断剂的可行性。拟议的研究需要验证 DHEAS 是前列腺癌细胞内分泌 T 和 DHT 的重要前体来源的概念。研究结果将深入了解如何通过靶向 DHEAS 转运蛋白、STS 和 STS 调节因子来阻止前列腺癌细胞使用 DHEAS，从而促进更完整的雄激素剥夺治疗。