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

 描述(申请人提供)：前列腺癌(PCa)是一种破坏性疾病，影响大量男性。雄激素剥夺疗法(ADT)几十年来一直是治疗复发和晚期PCa的中心主题，但没有患者通过这种方法被治愈。去势耐受前列腺癌(CRPC)的发展和进展仍然是一个主要的治疗挑战，因为即使是FDA新批准的二线ADT治疗(阿比特龙和苯扎鲁胺)也只能提供有限的生存益处(3-6个月)。不仅CRPC正在迅速适应这些治疗方法，而且CRPC(与其他实体肿瘤一样)是异质性的，一些肿瘤没有反应。一种普遍的假设是雄激素受体(AR)信号的持续存在是这种干预失败的原因，而主流的临床发展是实现AR信号的完全阻断。然而，AR调节前列腺癌细胞的生长，也调节前列腺上皮/癌细胞的分化。在体外、体内和患者中，超生理水平的睾酮(High-T)实际上被证明抑制了传统ADT失败的CRPC的生长，而不是促进生长。我们假设单独使用High-T和/或与度他雄胺联合使用将抑制阿比特龙耐药(Abir)Pca，并使肿瘤对阿比特龙(Abi)治疗重新敏感。我们的目标是进行临床前研究，以了解使用不同的Abir CRPC LuCaP异种移植治疗高温的疗效，并深入了解高温反应和/或耐药的机制。这些研究旨在填补我们对超生理性AR信号在CRPC中作用的理解上的一个重要空白。这些研究产生的信息可能会极大地改变我们对CRPC治疗的看法。

 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.