Targeting key orphan nuclear receptor in lethal prostate cancer

 描述(申请人提供)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。大多数进展到所谓的转移性去势抵抗PCA或mCRPC的肿瘤对包括苯扎鲁胺在内的第二代疗法产生耐药性，后者通常是无法治愈的。大量研究表明，雄激素受体(AR)在疾病发展过程中起着关键作用。重要的是，AR的mRNA和蛋白，包括其选择性剪接变异体，在大多数CRPC肿瘤中高度过度表达，这是导致耐药性的主要原因。因此，迫切需要更有效的治疗方法来抑制AR基因的异常表达，为PCa患者提供持续的益处。我们最近发现，核受体家族成员和治疗人类自身免疫性疾病的药物靶点RORg在转移性前列腺癌中高表达和扩增。我们进一步发现，我们等人发现的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。进一步研究发现，RORg可直接激活AR基因的表达。在这一应用中，我们提议通过实验严格检验以下假设：(1)RORg通过直接上调AR和肿瘤雄激素合成程序来驱动CRPC耐药；(2)通过RORg选择性抑制剂靶向RORg对治疗耐药的CRPC是有效的。我们将首先 确定RORg促进AR基因表达的作用机制。然后，我们将使用包括PDX在内的不同模型，检查RORg抑制剂在阻止CRPC肿瘤生长和转移方面的有效性，以及在使肿瘤对当前治疗方法如阿比特龙和苯扎鲁胺增敏方面的效果。我们还将采用基因组学的方法来挖掘和确定RORg在控制肿瘤雄激素合成和EMT计划中的作用。RORg还没有明确地与任何类型的癌症有关。因此，这项研究将是开创性的 有好几种方法。它将首次将RORg确立为致死性CRPC的主要驱动力，将其特异性抑制物确立为有效的AR基因和肿瘤阻滞剂，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利益，让它们重新调整自己的用途 抗自身免疫的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.