A Novel Drug Target for Aggressive Prostate Cancer

转移性去势抵抗性前列腺癌（mCRPC）通常发生在骨骼和软组织中 其特征是雄激素受体（AR）和组成型活性AR变体的表达增强 例如AR-V7。CRPC细胞中AR-V7的转录组分析鉴定了CRPC细胞中AR-V7的表达增加。 血管收缩剂和G蛋白偶联受体，精氨酸加压素受体-1a（AVPR 1a）。分析 公开的人类数据库显示， mCRPC与原发性PC肿瘤相比。选择性去除AVPR 1a降低CRPC细胞增殖。 相反，AVPR 1a在雄激素依赖性PC中的表达在体外赋予去势抵抗性生长， 和体内。与AVPR 1a信号在mCRPC中的潜在作用一致，mCRPC是 AVPR 1a，精氨酸加压素（AVP），刺激CRPC细胞迁移和侵袭。最重要的是， 使用临床上安全、有效且可口服的AVPR 1a拮抗剂瑞伐普坦抑制AVPR 1a， 在两种不同的体内异种移植模型中， CRPC和另一个是晚期骨转移模型。在后一种模型中，relcovaptan也减少了 体内mCRPC刺激的骨病变形成。PC引起的骨重建是疼痛的主要原因 和病理性骨折。根据这些初步结果，本提案将 研究AVPR 1a是最致命的PC形式的治疗靶点的假设， 疾病本提案的目的是描述AVPR 1a的调节机制， 驱动mCRPC，并评价安全有效的AVPR 1a拮抗剂在 mCRPC。将处理以下具体目标：目标1。剖析AVPR 1a和 AR/AR-V7; Aim 2.探讨AVPR 1a在mCRPC侵袭和早期转移中的作用;目的3.确定 AVPR 1a在骨微环境中mCRPC晚期转移生长中的作用。这些目标将 评估瑞伐普坦联合标准治疗雄激素剥夺疗法和化疗， 稳健的CRPC动物模型代表了从早期侵袭到晚期转移性生长的连续体。甚至 “最佳”化疗方案，通常是医学肿瘤学家治疗mCRPC的最后一种选择， 具有有限的功效和相当大的毒性。可以与较低剂量组合起作用的化合物 化疗是一种迫切且未满足的临床需求。AVPR 1a拮抗剂如瑞伐普坦可能是有用的 不仅在抑制mCRPC的进展和生长方面而且在防止过度的破骨细胞活性方面， 与mCRPC相关的骨吸收和病理性骨折瑞伐普坦的既往检查 人类临床试验（非癌症疾病）意味着这种化合物可以更快地测试， mCRPC临床试验，因为已经在人体中确定了剂量、安全性和疗效。因此， 该项目具有非常快速地转化为临床治疗mCRPC的潜力。

Metastatic castration resistant prostate cancer (mCRPC) commonly occurs in the skeleton and soft tissues and is hallmarked by enhanced expression of androgen receptor (AR) and constitutively active AR variants such as AR-V7. Transcriptome analyses of AR-V7 in CRPC cells identified increased expression of the vasoconstrictor and G protein-coupled receptor, arginine vasopressin receptor-1a (AVPR1a). Analysis of public human databases revealed significantly higher levels of AVPR1a mRNA in human specimens of mCRPC compared to primary PC tumors. Selective depletion of AVPR1a decreased CRPC cell proliferation. Conversely, expression of AVPR1a in androgen dependent PC conferred castration resistant growth in vitro and in vivo. Consistent with a potential role of AVPR1a signaling in mCRPC, the physiologic ligand for AVPR1a, arginine vasopressin (AVP), stimulated CRPC cell migration and invasion. Most importantly, inhibition of AVPR1a using relcovaptan, a clinically safe, effective and orally available AVPR1a antagonist, resulted in decreased CRPC growth in two distinct in vivo xenograft models, one representing newly emergent CRPC and the other a model of late stage bone metastasis. In the latter model, relcovaptan also diminished mCRPC-stimulated formation of bone lesions in vivo. PC-induced bone remodeling is a major cause of pain and pathological fracture in men with mCRPC. Based on these preliminary results, this proposal will investigate the hypothesis that AVPR1a is a therapeutic target for the most deadly form of PC, metastatic disease. The objectives of this proposal are to delineate the mechanisms by which AVPR1a is regulated and drives mCRPC and to evaluate the therapeutic potential of a safe and effective AVPR1a antagonist in mCRPC. The following specific aims will be addressed: Aim 1. Dissect cross talk between AVPR1a and AR/AR-V7; Aim 2. Interrogate the role of AVPR1a in mCRPC invasion and early metastasis; Aim 3. Determine the role of AVPR1a in mCRPC late metastatic growth in the bone microenvironment. These objectives will assess relcovaptan in conjunction with standard of care androgen deprivation therapy and chemotherapy in robust CRPC animal models representing the continuum from early invasion to late metastatic growth. Even “optimal” chemotherapy regimens, often the last line of options for the medical oncologist in treating mCRPC, have limited efficacy and considerable toxicity. Compounds that can work in combination with lower dose chemotherapy are an urgent and unmet clinical need. AVPR1a antagonists such as relcovaptan may be useful not only in inhibiting progression and growth of mCRPC but also in preventing excessive osteoclast activity, bone resorption and pathological fracture associated with mCRPC. The prior examination of relcovaptan in human clinical trials (for non-cancer disorders) means that this compound can be more rapidly tested in mCRPC clinical trials because dose, safety and efficacy have already been established in humans. Thus, this project has the potential for very rapid translation to the clinic for the treatment of mCRPC.