Therapeutic targeting of orphan NR in ER-negative breast cancer

摘要 尽管三阴性乳腺癌（TNBC）经常出现，但仍然缺乏有效的靶向治疗 表现为预后差的侵袭性疾病。TNBC亚型显示罕见或低病理完全性 新辅助化疗的缓解率（pCR）。尽管有新获得的肿瘤基因组学数据， 尚未发现或确定易于采取行动的有效治疗目标。 我们最近的数据挖掘和其他肿瘤分析显示，RORC/RORγ，一个孤儿成员， 转录因子的核受体家族在超过30%的TNBC中扩增或过表达，并且其 过度表达与不良结果显著相关。我们的功能研究表明， TNBC细胞的生长和存活所需的，它的抑制剂，我们最近开发的，高度 在相对低的剂量下有效地选择性杀死TNBC细胞并阻止肿瘤生长和转移， 没有明显的毒性通过其他的初步研究，我们假设过表达和/或 RORγ的超活化通过一种新的胆固醇前馈回路驱动TNBC进展， 用有效的肿瘤选择性小分子抑制剂靶向RORγ，单独或与 化疗，可以是TNBC的一种新的和有效的治疗策略。该假设将在3中进行检验 具体目标：目标1将确定过表达的RORγ驱动肿瘤生长和治疗抗性 通过其在重编程脂质/胆固醇代谢中的功能;目标2将建立诱导脂质/胆固醇代谢的方法。 表观遗传开关是RORγ抑制剂的上级抗TNBC效力的基础，Aim 3将彻底 使用PDX和其他肿瘤模型检查优化的抑制剂的抗肿瘤功效。成功 拟议研究的完成将首次将RORγ确立为TNBC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.