The role of HDAC2 in hormone therapy resistance

描述(由申请人提供)：雌激素受体(ER)的调节一直是乳腺癌妇女最成功的治疗策略之一。两种最常用的雌激素受体抑制方法是使雌激素受体与抗雌激素药物(如他莫昔芬)竞争结合，或使用芳香化酶抑制剂减少靶组织中雌激素的局部产生。然而，在肿瘤最初表达ER的患者中，超过50%的患者对激素治疗出现抵抗，并且很高比例的肿瘤是先天抵抗的。除了他莫昔芬之外，引入新型抗雌激素的广泛努力，如选择性雌激素受体下调调节剂(SERD)fulvestrant或选择性雌激素调节剂(SERM)雷洛昔芬，取得的成功有限。一个新出现的提高激素治疗效果的策略涉及ER信号的表观遗传调节。我们和其他实验室的临床前研究表明，在他莫昔芬治疗中添加HDAC抑制剂可以逆转他莫昔芬的耐药性，并协同诱导细胞死亡。此外，在我们小组最近完成的一项临床试验中，激素治疗耐药肿瘤的一部分患者在接受这种联合治疗时肿瘤持续消退，这为HDAC抑制作为逆转激素治疗耐药的方法提供了临床证据。伴随这项试验的外周血单核细胞的相关研究表明，有反应的患者组蛋白乙酰化和HDAC2的表达比没有治疗受益的患者更高。为了确定与他莫昔芬协同作用的相关HDAC靶点，我们证明了HDAC2的siRNA缺失足以增强他莫昔芬的细胞毒作用，并调节ER阳性乳腺癌细胞中的雌激素信号。HDAC2抑制ER调节的促凋亡基因，从而使SERM即使在ER超敏和内源性雌激素水平较高的情况下也能发挥其抗激动剂作用。因此，我们推测HDAC2在激素治疗耐药中起重要作用，其选择性缺失可能为逆转抗雌激素治疗耐药提供一种新的策略。在这一应用中，我们试图确定HDAC2作为激素敏感型和激素抵抗型乳腺癌治疗靶点和预测反应标志物的相关性。在特定的目的1中，我们将在体外模型中确定HDAC2抑制-抗雌激素治疗联合治疗乳腺癌的最佳治疗环境。在特定的AIM 2中，我们将评估患者样本中HDAC的表达，并确定它们作为预测联合治疗反应的标志物的潜力。在特定的目标3中，我们将使用体内乳腺癌异种移植模型评估HDAC2耗竭单独或联合抗雌激素治疗诱导原发肿瘤消退和减少转移的能力。 公共卫生相关性：在美国，转移性乳腺癌患者的中位生存期约为24个月，每年死亡人数超过4万人。对于乳腺癌患者来说，激素治疗是最成功、毒性最小的方法之一。然而，超过50%的患者先天对激素治疗产生抵抗，或者随着时间的推移而变得对治疗产生抵抗。我们的临床前和临床数据表明，HDAC抑制剂对雌激素受体的表观遗传调节可能会引入一种逆转激素治疗耐药性的新策略。这一应用将决定将HDAC抑制剂整合到激素治疗中的最佳临床环境。

DESCRIPTION (provided by applicant): Modulation of the estrogen receptor (ER) has been one of the most successful treatment strategies in women with breast cancer. The two most commonly used methods of ER inhibition are either competitive binding of the ER with anti-estrogens (e.g. tamoxifen) or to decrease the local production of estrogen in target tissues using an aromatase inhibitor. However, resistance to hormonal therapy emerges in more than 50% of patients whose tumors initially express ER, and a high percentage of tumors are a priori resistant. An extensive effort to introduce novel anti-estrogens, such as the selective estrogen receptor down-regulator (SERD) fulvestrant, or the selective estrogen modulator (SERM) raloxifene, has had limited success beyond that achieved with tamoxifen. An emerging strategy to enhance the efficacy of hormone therapy involves epigenetic modulation of ER signaling. Preclinical studies from our and other laboratories have shown that the addition of an HDAC inhibitor to tamoxifen treatment reverses tamoxifen resistance and synergistically induces cell death. Furthermore, in a recently completed clinical trial by our group, a subset of patients with hormone therapy resistant tumors had durable tumor regression when treated with this combination, providing clinical evidence for HDAC inhibition as an approach for reversing hormone therapy resistance. Correlative studies accompanying this trial in peripheral blood mononuclear cells suggest that histone acetylation and HDAC2 expression was higher in patients with a response than those without treatment benefit. In an effort to determine the relevant HDAC targets for synergy with tamoxifen, we demonstrated that siRNA depletion of HDAC2 was sufficient to potentiate the cytotoxic effects of tamoxifen and modulate estrogen signaling in ER- positive breast cancer cells. HDAC2 represses ER regulated pro-apoptotic genes and thus its inhibition allows SERMs to exert their anti-agonistic effects even in settings of ER hypersensitivity and high endogenous estrogen levels. Therefore, we hypothesize that HDAC2 plays an important role in hormone therapy resistance and its selective depletion may offer a novel strategy to reverse resistance to anti-estrogen therapy. In this application, we seek to determine the relevance of HDAC2 as a therapeutic target and predictive marker of response for the treatment of hormone sensitive and hormone resistant breast cancer. In SPECIFIC AIM 1 we will define the optimal therapeutic setting for combined HDAC2 inhibition-anti-estrogen therapy for the treatment of breast cancer in in vitro models. In SPECIFIC AIM 2, we will evaluate HDAC expression in patient samples and determine their potential as a predictive marker for response to this combined therapy. In SPECIFIC AIM 3 we will evaluate the ability of HDAC2 depletion either alone or in combination with anti- estrogen therapy to induce the regression of primary tumors and to reduce metastases using in vivo breast cancer xenograft models. PUBLIC HEALTH RELEVANCE: Patients with metastatic breast cancer have a median survival of approximately 24 months and account for over 40,000 deaths per year in the United States. Hormonal therapy is one of the most successful and least toxic modalities for patients with breast cancer. However more than 50% of the patients are a priori resistant to hormone therapy, or become therapy resistant over time. Our preclinical and clinical data suggest that epigenetic modulation of the estrogen receptor by HDAC inhibitors may introduce a novel strategy to reverse hormone therapy resistance. This application will determine the optimal clinical setting to integrate HDAC inhibitors into hormonal therapy.