Exploring high-does testosterone as a potential treatment for abiraterone-resistant prostate cancer

探索高剂量睾酮作为阿比特龙耐药性前列腺癌的潜在治疗方法

• 批准号: 9095803
• 负责人: EVA COREY
• 金额: $ 16.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095803
• 关键词: Accounting; Address; Affect; Androgen Receptor; Androgens; Apoptosis; Appearance; Applications Grants; Biopsy; Castration; Cell Cycle Arrest; Characteristics; Clinical; Data; Development; Disease; Dose; Dutasteride; Epithelium; Exhibits; FDA approved; Failure; Future; Genes; Glucocorticoid Receptor; Growth; Harvest; Heterogeneity; In Vitro; Intervention; Ligands; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Modality; Modeling; Molecular Target; Monitor; Neoplasm Metastasis; PTEN gene; Pathway interactions; Patients; Physiological; Prostate; Prostatic Neoplasms; Publishing; Quality of life; Receptor Signaling; Recurrence; Resistance; Resistance development; Resources; Role; Serum; Solid Neoplasm; Staging; TMPRSS2 gene; Testing; Testosterone; Therapeutic Intervention; Tissues; Translations; Variant; Xenograft procedure; abiraterone; base; cancer cell; castration resistant prostate cancer; deprivation; effective therapy; efficacy testing; improved; in vivo; insight; men; patient stratification; pre-clinical; preclinical efficacy; preclinical study; prostate cancer cell; prostate cancer cell line; public health relevance; response; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a devastating disease that affects a large number of men. Androgen deprivation therapy (ADT) has been the central theme in the treatment of recurrent and advanced PCa for many decades, yet no patients were cured by this means. The development and progression of castration-resistant PCa (CRPC) remains a major treatment challenge because even the newly FDA-approved second-line ADT treatments (abiraterone and enzalutamide) provide limited survival benefits (3-6 months). Not only that CRPC is rapidly adapting to these therapies, but also CRPC (like other solid tumors) is heterogeneous and some tumors do not respond. A common assumption is that the persistence of androgen receptor (AR) signaling accounts for the failure of this intervention, and the prevailing clinical development is to achieve a complete blockade of AR signaling. However, AR regulates growth of PCa cells and also differentiation of prostate epithelium/cancer cells. Instead of promoting growth, supra physiological levels of testosterone (high-T) have actually been shown to inhibit growth of CRPC that failed traditional ADT in vitro, in vivo, and in patients We hypothesize that high-T alone and/or with dutasteride will inhibit abiraterone-resistant (AbiR) PCa, and re-sensitize the tumor to abiraterone (Abi) treatment. Our objective is to perform preclinical studies to investigate the efficacy of the high-T therapy using different AbiR CRPC LuCaP xenografts and to get insight into the mechanisms underlying high-T responsiveness and/or resistance. The proposed studies intend to fill a critical void in our understanding of the roles of supra-physiological AR signaling in CRPC. The information generated from these studies may substantially alter our views of treatments for CRPC.

 描述（应用程序提供）：前列腺癌（PCA）是一种影响大量男性的毁灭性疾病。数十年来，雄激素剥夺治疗（ADT）一直是复发和晚期PCA治疗的中心主题，但是没有通过这种方式治愈患者。耐castration PCA（CRPC）的发展和进展仍然是一个主要的治疗挑战，因为即使是新近FDA批准的二线ADT治疗（阿比里酮和恩扎拉塔米酰胺）也提供了有限的生存益处（3-6个月）。不仅CRPC迅速适应了这些疗法，而且CRPC（与其他实体瘤一样）也是异质性的，有些肿瘤没有反应。一个普遍的假设是，雄激素受体（AR）信号传导的持久性解释了这种干预措施的失败，并且主要的临床发育是实现AR信号传导的完全阻断。但是，AR调节PCA细胞的生长以及前列腺上皮/癌细胞的分化。实际上已经证明，上超睾丸激素的身体水平没有促进增长，而是显示出在体外，体内抑制传统ADT失败的CRPC的增长，而在患者中，我们假设单独使用高位和/或与荷雄胺相比会抑制abiraterone-抗性（Abir）PCA（Abir）PCA，以及对abirateRONE（Abirater）的治疗。我们的目标是进行临床前研究，以使用不同的ABIR CRPC LucaP异种移植物研究高位治疗的效率，并深入了解高T响应性和/或抗性的机制。拟议的研究旨在填补我们对CRPC上生理AR信号的作用的关键空隙。这些研究产生的信息可能会大大改变我们对CRPC治疗的看法。