Targeting key orphan nuclear receptor in lethal prostate cancer

 转移性前列腺癌（PCa）仍然是美国男性癌症相关死亡的主要原因之一。大多数进展为转移性去势抵抗性PCa或mCRPC的肿瘤对第二代治疗药物（包括enzalutamide）产生耐药性，通常无法治愈。大量研究表明雄激素受体（AR）在疾病进展中起着关键作用。重要的是，AR mRNA和蛋白质，包括其可变剪接变体，在大多数CRPC肿瘤中高度过表达，这主要导致耐药性。因此，迫切需要能够抑制异常AR基因表达并为PCa患者提供持续益处的更有效的治疗剂。我们最近发现，RORg，一个核受体家族成员和人类自身免疫性疾病的药物靶点，在转移性前列腺癌中过表达和扩增。我们进一步发现，由我们和其他人鉴定的RORg选择性小分子抑制剂可以有效地抑制CRPC异种移植模型的肿瘤生长，而对宿主动物没有明显的不良影响。进一步的研究表明，RORg直接激活AR基因的表达。在本申请中，我们提出了严格检验以下假设的实验：（1）RORg通过直接上调AR和肿瘤雄激素合成程序驱动CRPC耐药性，以及（2）通过RORg选择性抑制剂靶向RORg可有效治疗耐药性CRPC。我们将首先 探讨RORg促进AR基因表达的作用机制。使用包括PDX在内的不同模型，我们将检查RORg抑制剂在阻断CRPC肿瘤生长和转移以及使肿瘤对当前治疗剂如阿比特龙和恩杂鲁胺敏感方面的功效。我们还将采用基因组学方法来挖掘和定义RORg在控制肿瘤雄激素合成和EMT程序中的作用。RORg尚未明确涉及任何类型的癌症。因此，这项研究将是开创性的， 几种方式。它将首次确立RORg作为致死性CRPC的主要驱动因素，其特异性抑制剂作为有效的AR基因和肿瘤阻断剂，从而确立RORg作为新的癌症治疗靶点。它还将激起制药公司的兴趣，使其“重新利用” 抗自身免疫RORg抑制剂作为新一代前列腺癌药物。

 DESCRIPTION (provided by applicant) Metastatic prostate cancer (PCa) remains to be one of the leading causes of cancer-related death in U.S. men. Most tumors that advance to so-called metastatic castration-resistant PCa or mCRPC develop resistance to the 2nd generation therapeutics including enzalutamide, which is generally incurable. Numerous studies clearly indicate that androgen receptor (AR) plays a pivotal role in the disease progression. Importantly, AR mRNA and protein, including its alternatively spliced variants, are highly overexpressed in most CRPC tumors, which contribute majorly to resistance. Therefore, there is an urgent need of more effective therapeutics that can suppress the aberrant AR gene expression and provide sustained benefits to PCa patients. We recently discovered that RORg, a nuclear receptor family member and a drug target for human autoimmune diseases, is overexpressed and amplified in metastatic PCa. We further discovered that RORg-selective, small molecule inhibitors identified by us and others can potently inhibit tumor growth of CRPC xenograft models, without discernable adverse effects on host animals. Further studies revealed that RORg directly activates AR gene expression. In this application, we propose experiments to rigorously test the hypotheses that (1) RORg drives CRPC resistance through directly up-regulating AR and the tumor androgen synthesis program and that (2) targeting RORg by the RORg-selective inhibitors is efficacious for treatment of the therapy-resistant CRPC. We will first determine the functional mechanism of RORg in promoting AR gene expression. Using different models including PDXs, we will then examine the efficacy of the RORg inhibitors in blocking CRPC tumor growth and metastasis, and in sensitizing the tumors to the current therapeutics such as abiraterone and enzalutamide. We will also take genomics approach to unearth and define the role of RORg in control of tumor androgen synthesis and EMT programs. RORg has not been explicitly implicated in any type of cancers. Thus, this study will be ground- breaking in several ways. It will, for the first time, establish RORg as a major driver of lethal CRPC, its specific inhibitors as effective AR gene and tumor blockers, and thus establish RORg as a new cancer therapeutic target. It will also stir the interests of pharmaceuticals to "re-purpose" their anti- autoimmune RORg inhibitors as a new generation of PCa drugs.