The role of HDAC2 in hormone therapy resistance

描述（由申请人提供）：调节雌激素受体（ER）是乳腺癌女性最成功的治疗策略之一。两种最常用的ER抑制方法是ER与抗雌激素（例如他莫昔芬）的竞争性结合或使用芳香酶抑制剂减少靶组织中雌激素的局部产生。然而，超过50%的肿瘤最初表达ER的患者出现对激素治疗的抗性，并且高百分比的肿瘤是先验抗性的。引入新型抗雌激素的广泛努力，如选择性雌激素受体下调剂（SERD）氟维司群或选择性雌激素调节剂（SERM）雷洛昔芬，在他莫昔芬之外取得的成功有限。增强激素治疗功效的新兴策略涉及ER信号传导的表观遗传调节。我们和其他实验室的临床前研究表明，在他莫昔芬治疗中加入HDAC抑制剂可逆转他莫昔芬耐药性，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，一部分激素治疗耐药肿瘤患者在接受这种组合治疗时具有持久的肿瘤消退，为HDAC抑制作为逆转激素治疗耐药性的方法提供了临床证据。在外周血单个核细胞中进行的相关研究表明，组蛋白乙酰化和HDAC 2表达在有应答的患者中高于无治疗获益的患者。为了确定与他莫昔芬协同作用的相关HDAC靶标，我们证明了HDAC 2的siRNA消耗足以增强他莫昔芬的细胞毒性作用并调节ER阳性乳腺癌细胞中的雌激素信号传导。HDAC 2抑制ER调节的促凋亡基因，因此其抑制允许SERM甚至在ER超敏性和高内源性雌激素水平的情况下发挥其抗激动作用。因此，我们假设HDAC 2在激素治疗抵抗中起重要作用，其选择性缺失可能提供一种逆转抗雌激素治疗抵抗的新策略。 在本申请中，我们试图确定HDAC 2作为治疗激素敏感性和激素抵抗性乳腺癌的治疗靶点和反应的预测标志物的相关性。在SPECIFIC AIM 1中，我们将定义HDAC 2抑制-抗雌激素联合疗法在体外模型中治疗乳腺癌的最佳治疗环境。在SPECIFIC AIM 2中，我们将评估患者样本中的HDAC表达，并确定其作为该联合治疗反应的预测标志物的潜力。在SPECIFIC AIM 3中，我们将使用体内乳腺癌异种移植模型评估HDAC 2耗竭单独或与抗雌激素治疗组合诱导原发性肿瘤消退和减少转移的能力。

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.