Prostate-Specific Androgen Transporters are the Missing Target for Complete ADT

前列腺特异性雄激素转运蛋白是完整 ADT 缺失的目标

基本信息

批准号：
9027508
负责人：
GARY Joseph SMITH
金额：
$ 39.23万
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：
2015
资助国家：
美国
起止时间：
2015-12-09 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027508
关键词：
ATP-Binding Cassette Transporters Acute Adjuvant Therapy Adrenal Glands Adverse effects Androgen Antagonists Androgen Metabolism Androgen Receptor Androgens Architecture Benign Biological Models Blood CCL21 gene Castration Cell Separation Cells Complement Dehydroepiandrosterone Sulfate Disease Endothelial Cells Environment Enzymes Epithelial Cells Experimental Models Failure Fluorescence-Activated Cell Sorting Gene Expression Genes Goals Human Incubated Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Transport Proteins Metabolism Modality Modeling Molecular Molecular Profiling Morbidity - disease rate Organ Oxidoreductase Parents Pathway interactions Permeability Pre-Clinical Model Process Production Prostate Prostatectomy Receptor Activation Receptor Signaling Recurrence Research SRD5A2 gene Source Specimen Staging Stanolone Steroids Testosterone Therapeutic Tissues Transplantation Transplanted tissue Treatment Efficacy base dehydroepiandrosterone deprivation design differential expression driving force efflux pump humanized SCID mouse humanized mouse improved in vitro Model in vivo in vivo Model inhibitor/antagonist interpatient variability interstitial novel prevent prostate cancer cell public health relevance receptor-mediated signaling research study standard of care sulfurtransferase therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Androgen Deprivation Therapy (ADT) has been the standard-of-care for advanced prostate cancer for almost 70 years, but is neither curative nor durable. Furthermore, ADT is not an option for treatment of organ-localized prostate cancer because of collateral systemic morbidity. The hypothesis of this project is ... interdiction of prostate endothelial cell-specific uptake and trans-cellular transport of circulating adrenal androgens through the blood-prostate barrier, will complement ADT to provide a curative/durable therapy for organ-localized and advanced prostate cancer. The experimental goals of this project are to determine if dehydroepiandrosterone-sulfate (DHEA-S) represents an endogenous substrate for intracrine dihydrotestosterone (DHT) production and AR-activation by prostate epithelial cells in both the presence and absence of circulating testosterone (ADT), if intracrine metabolism of DHEA-S→DHT is mediated through a steroid 5α-reductase 1 (SRD5A1)- or a SRD5A2-dependent mechanism, and if prostate endothelial cell- specific mechanisms of DHEA-S uptake, transport or efflux represent prostate endothelial cell-specific therapeutic targets to make ADT more effective. Aim 1 will determine inter-patient variability in up-take and metabolism of circulating testosterone and DHEA-S, the expression profiles of genes associated with androgen metabolism in prostate endothelial cells and prostate cancer/prostate epithelial cells, the short-term effect of testosterone-deprivation on these processes, and whether intracrine metabolism of DHEA-S → DHT is mediated by SRD5A1 or SRD5A2. Aim 2 will define the molecular mechanisms that mediate uptake, trans-cellular transport and efflux of DHEA-S in human prostate endothelial cells and prostate cancer/prostate epithelial cells, and identify the metabolites effluxed by prostate endothelial cells that serve as precursors for intracrine conversion to DHT in prostate cancer/prostate epithelial cells. Aim 3 wil determine whether interdiction of adrenal androgen uptake/metabolism/efflux by prostate endothelial cells and/or prostate cancer/prostate epithelial cells using inhibitors of SLCO/SLC uptake transporters, ABC efflux pumps, STS and SRD5A1&2 enhances the ability of testosterone-deprivation (ADT) to block intracrine production of DHT. Aims 1 and 2 will be conducted in ex vivo and in vitro model systems using small pieces of intact freshly procured prostate tissue and primary cultures of prostate endothelial cells and prostate cancer cells. Aim 3 will utilize a unique preclinical model in which freshly procured prostate tissue transplanted to "humanized" mouse hosts as an in vivo model, where prostate tissue architecture is maintained, and all cell compartments, including prostate endothelial cells, are human.

描述（由适用提供）：将近70年来，雄激素剥夺治疗（ADT）一直是晚期前列腺癌的护理标准，但既不是治愈性也不耐用。此外，由于附带系统发病率，ADT不是治疗有组织的前列腺癌的选择。该项目的假设是...前列腺内皮细胞特异性的摄取和通过血液前屏障的循环肾上腺雄激素的跨细胞转运，将补充ADT，以提供一种治疗/耐用的治疗疗法，以用于器官定位和晚期前列腺癌。该项目的实验目标是确定脱氢表硫硫酸盐（DHEA-S）是否代表了内源性二氢睾丸激素（DHT）的内源底物（DHT）的产生（DHT）的产生和AR-AR激活，前列腺上皮细胞在循环睾丸激素（ADT）的存在下，Ifractore nistried senteried senterabine-senteried senterabine sertied nspolibilist dheabolislist of dheaboliass-nefied sepline contied nified in Isbiried sertried senteried senteried sertied of。 5α-还原酶1（SRD5A1） - 或SRD5A2依赖机制，以及DHEA-S摄取，转运或外排的前列腺内皮细胞特异性机制，代表前列腺内皮细胞特异性治疗靶标，以使ADT更有效。 Aim 1 will determine inter-patient variability in up-take and metabolism of circulating testosterone and DHEA-S, the expression profiles of genes associated With androgen metabolism in prostate endothelial cells and prostate cancer/prostate epithelial cells, the short-term effect of testosterone-deprivation on these processes, and whether intracrine metabolism of DHEA-S → DHT is mediated by SRD5A1或SRD5A2。 AIM 2将定义人类前列腺内皮细胞中DHEA-S培养基，细胞运输和外排的分子机制，并在前列腺癌/前列腺上皮细胞中识别由前列腺内皮细胞排出的代谢产物，这些细胞用作前列腺内皮细胞的代谢产物前列腺癌/前列腺上皮细胞中内部转化为DHT的前体。 AIM 3 WIL确定使用SLCO/SLC摄取蛋白的抑制剂，ABC外排泵，STS和SRD5A1和2的抑制剂，是否可以通过（增强testern intertivation in Testertan intertivation testertan intertivation testern intertivation intertivations intoss intertivations intertivations intertivation intertivations（addo）/SLC泵送泵，ABC外排泵，STS和SRD5A1和2增强testoster inter inter inter的能力（增强block inter的能力）。 AIM 1和2将在离体和体外模型系统中使用一小部分新鲜采购的前列腺组织以及前列腺内皮细胞和前列腺癌细胞的原发性培养。 AIM 3将利用独特的临床前模型，其中新鲜采购的前列腺组织移植到 “人性化”小鼠宿主是一种体内模型，在该模型中保持前列腺组织结构，并且所有细胞室（包括前列腺内皮细胞）都是人类。