Understanding Resistance to Next Generation Antiandrogens

描述(由申请人提供)：在过去的几年里，我们对前列腺癌的了解有了很大的增长。从治疗的角度来看，去势抵抗前列腺癌(CRPC)主要是由于雄激素受体(AR)信号通路的重新激活。这导致了新的靶向疗法，这些疗法刚刚获得或接近FDA的批准，但这些都有实质性的缺陷。其中之一是我们实验室发现和开发的新型抗雄激素MDV3100(Tran等人科学，2009)。大约一半的CRPC患者患有耐药疾病，而大多数最初有反应的人随着时间的推移获得了耐药性。我们在两个人类前列腺癌模型系统中进行了对MDV3100获得性耐药性的体外和体内筛选。对数十对药物敏感和耐药的转录组分析揭示了一种新的、常见的耐药机制。与第一代抗雄激素治疗耐药的主要机制不同，第一代抗雄激素疗法是由于AR上调而发生的(Chen等人Nat Med 2004)，对MDV3100的耐药性始终与糖皮质激素受体(GR)上调有关。此外，在耐药肿瘤中，许多AR靶基因仍然被抑制，这表明经典的AR信号通路仍然被MDV3100抑制。然而，一些AR靶基因的表达得到了恢复，但表达方式现在依赖于GR。我们提出了一个模型，通过核受体旁路(GR取代AR)发生对MDV3100(可能还有其他下一代抗雄激素)的耐药性。在这里，我们将探索GR选择性激活某些AR靶基因的分子基础(AIM 1)，GR、AR和GR/AR靶基因SGK1在维持耐药中的功能作用(AIM 2)，以及这些发现在患者治疗开始和复发时获得的循环肿瘤细胞中的临床相关性(AIM 3)。

DESCRIPTION (provided by applicant): Our understanding of prostate cancer has grown enormously over the past several years. From a treatment perspective, it has become clear that castration-resistant prostate cancer (CRPC) mainly owes this property to reactivation of androgen receptor (AR) signaling pathways. This has led to new targeted therapies, which have just received or are nearing FDA approval, but these have substantial shortcomings. One of these is the novel antiandrogen MDV3100 discovered and developed by our lab (Tran et al Science 2009). Roughly half of CRPC patients present with therapy-resistant disease and most of those who initially respond acquire resistance over time. We have conducted in vitro and in vivo screens of acquired resistance to MDV3100 in two human prostate cancer model systems. Transcriptome analysis of dozens of drug-sensitive and drug-resistant pairs revealed a novel, common resistance mechanism. Unlike the primary mechanism of resistance to first generation antiandrogen therapy which occurs due to upregulation of AR (Chen et al Nat Med 2004), resistance to MDV3100 is consistently associated with upregulation of the glucocorticoid receptor (GR). Furthermore, many AR target genes remain inhibited in drug-resistant tumors, indicating that the classical AR signaling pathway remains "inhibited" by MDV3100. However, expression of some AR target genes is restored but in a manner that is now dependent on GR. We propose a model whereby resistance to MDV3100 (and perhaps other next generation antiandrogens) occurs through nuclear receptor bypass (GR replaces AR). Here we will explore the molecular basis by which GR selectively activates certain AR target genes (Aim 1), the functional role of GR, AR and the GR/AR target gene SGK1 in maintaining drug resistance (Aim 2), and the clinical relevance of these findings in circulating tumor cells obtained from patients t treatment start and at relapse (Aim 3).