The role of HDAC2 in hormone therapy resistance

HDAC2 在激素治疗抵抗中的作用

• 批准号: 8517452
• 负责人: Pamela N. Munster
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517452
• 关键词: Accounting; Acetylation; Apoptotic; Area; Aromatase Inhibitors; Breast Cancer Cell; Breast Cancer Treatment; Cell Death; Cessation of life; Clinical; Clinical Data; Clinical Trials; Competitive Binding; Correlative Study; Data; Diagnosis; Disease; Drug Evaluation; Epigenetic Process; Estrogen Antagonists; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Estrogens; Exemestane; Fulvestrant; Future; Genes; HDAC2 gene; Hematologic Neoplasms; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Hormones; Hypersensitivity; In Vitro; Laboratories; Letrozole; Methods; Modality; Neoplasm Metastasis; Patient Selection; Patients; Peripheral Blood Mononuclear Cell; Pharmacodynamics; Play; Premenopause; Primary Neoplasm; Production; Raloxifene; Receptor Inhibition; Receptor Signaling; Resistance; Role; Sampling; Selective Estrogen Receptor Modulators; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Tamoxifen; Testing; Therapeutic; Time; Tissues; Tumor Tissue; United States; Vorinostat; Woman; Xenograft Model; anastrozole; chemotherapy; cytotoxic; design; hormone therapy; improved; in vitro Model; in vivo; in vivo Model; malignant breast neoplasm; novel; novel strategies; pilot trial; pre-clinical; preclinical study; prospective; receptor expression; response; response marker; success; therapeutic target; therapy resistant; treatment response; treatment strategy; tumor

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.

描述（由申请人提供）：雌激素受体（ER）的调节一直是女性乳腺癌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）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 的患者出现了对激素治疗的耐药性，并且很大一部分肿瘤具有先验耐药性。人们在引入新型抗雌激素方面做出了广泛的努力，例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，但与他莫昔芬相比，取得的成功有限。增强激素治疗疗效的新兴策略涉及 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，在他莫昔芬治疗中添加 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，一部分患有激素治疗耐药性肿瘤的患者在接受这种联合治疗时出现了持久的肿瘤消退，这为 HDAC 抑制作为逆转激素治疗耐药性的方法提供了临床证据。伴随这项外周血单核细胞试验的相关研究表明，有缓解的患者组蛋白乙酰化和 HDAC2 表达高于没有治疗获益的患者。为了确定与他莫昔芬协同作用的相关 HDAC 靶标，我们证明 HDAC2 的 siRNA 耗竭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。 HDAC2 抑制 ER 调节的促凋亡基因，因此它的抑制使 SERM 即使在 ER 过敏和高内源性雌激素水平的情况下也能发挥其抗激动作用。因此，我们假设 HDAC2 在激素治疗抵抗中发挥重要作用，其选择性耗尽可能提供一种新的策略来逆转抗雌激素治疗的抵抗。 在此应用中，我们试图确定 HDAC2 作为激素敏感性和激素抵抗性乳腺癌治疗靶点和反应预测标记物的相关性。在具体目标 1 中，我们将定义 HDAC2 抑制与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，并确定其作为对该联合疗法反应的预测标记的潜力。在 SPECIFIC AIM 3 中，我们将使用体内乳腺癌异种移植模型评估单独或与抗雌激素疗法联合消除 HDAC2 诱导原发性肿瘤消退和减少转移的能力。