Therapeutic targeting of orphan NR in ER-negative breast cancer

摘要 三阴性乳腺癌(TNBC)仍然缺乏有效的靶向治疗，尽管TNBC经常 表现为侵袭性疾病，预后不佳。TNBC亚型表现罕见或低病理完全性 新辅助化疗的有效率(PCR率)。尽管新获得了肿瘤基因组学数据， 易于操作、治疗有效的目标尚未揭示或确定。 我们最近的数据挖掘和其他肿瘤分析显示，RORC/RORγ，一个 核受体转录因子家族，在超过30%的TNBC中扩增或过表达，其 过度表达与不良结局显著相关。我们的功能研究表明，它是 它是TNBC细胞生长和存活所必需的，而且我们最近开发的它的抑制剂是高度 在相对较低的剂量下，有效地选择性地杀伤TNBC细胞，阻止肿瘤的生长和转移， 没有明显的毒性。在其他初步研究中，我们假设过度表达和/或 RoRγ的过度激活通过一种新的胆固醇前馈环路推动肿瘤的进展 单独或联合使用有效的肿瘤选择性小分子抑制剂靶向RORγ 化疗是治疗TNBC的一种新的有效的治疗策略。这一假设将在3年内得到检验。 具体目标：目标1将确定过表达的RoRγ推动肿瘤生长和治疗耐药 通过其在脂类/胆固醇代谢重新编程中的作用；目标2将建立诱导 表观遗传转换是RoRγ抑制剂优越的抗肿瘤活性的基础，目标3将彻底 用PDX和其他肿瘤模型检测优化后的抑制剂的抗肿瘤效果。成功 拟议研究的完成将首次使RoRγ成为跨国公司的一个新的主要驱动力 和有效的治疗靶点。

ABSTRACT Triple-negative breast cancers (TNBC) still lack effective targeted therapy, despite the fact that TNBC often presents as invasive diseases with poor outcome. Subtypes of TNBC show rare or low pathological complete response (pCR) rates to neoadjuvant chemotherapies. Despite the newly acquired tumor genomics data, readily actionable, therapy-effective targets are yet to be revealed or established. Our recent data mining and other tumor analysis revealed that RORC/RORγ, an orphan member of the nuclear receptor family of transcription factors, is amplified or overexpressed in over 30% of TNBC and that its overexpression is significantly associated with poor outcomes. Our functional studies revealed that it is required for growth and survival of TNBC cells, and that its inhibitors, developed recently by us, are highly effective in killing TNBC cells selectively and stopping tumor growth and metastasis at relatively low doses, without overt toxicity. With other preliminary studies, we hypothesize that overexpression and/or hyperactivation of RORγ drives TNBC progression through a novel cholesteromic feed-forward loop and that targeting RORγ with a potent tumor-selective, small-molecule inhibitor, either alone or in combination with chemotherapy, can be a novel and effective therapeutic strategy for TNBC. The hypothesis will be tested in 3 specific aims: Aim 1 will establish that overexpressed RORγ drives tumor growth and therapeutic resistance through its function in reprogramming lipid/cholesterol metabolism; Aim 2 will establish that induction of an epigenetic switch underlies the superior anti-TNBC potency of the RORγ inhibitor, and Aim 3 will thoroughly examine the anti-tumor efficacy of the optimized inhibitor using PDX and other tumor models. Successful completion of the proposed studies should, for the first time, establish RORγ as a new, major driver of TNBC and effective therapeutic target.