The role of HDAC2 in hormone therapy resistance

HDAC2 在激素治疗抵抗中的作用

基本信息

批准号：
8073790
负责人：
Pamela N. Munster
金额：
$ 32.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8073790
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

项目摘要

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.

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，其选择性消耗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 作为治疗激素敏感性和激素抵抗性乳腺癌的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。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，每年导致 40,000 多人死亡。激素疗法是乳腺癌患者最成功且毒性最小的疗法之一。然而，超过 50% 的患者对激素治疗存在先验耐药性，或者随着时间的推移变得耐药。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。该应用将确定将 HDAC 抑制剂整合到激素治疗中的最佳临床环境。