Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activit

具有雌激素受体调节活性的组蛋白脱乙酰酶抑制剂

• 批准号: 8683414
• 负责人: Adegboyega Oyelere
• 金额: $ 16.27万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683414
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adverse effects; Antineoplastic Agents; Binding; Biochemical; Biodistribution; Breast Cancer Cell; Breast Cancer Model; Breast Carcinoma; Cancer cell line; Cell Line; Cell Nucleus; Cell Survival; Cell membrane; Cells; Cessation of life; Clinical; Clinical Trials; Correlation Studies; Cutaneous; Cytoplasm; Cytotoxic agent; Data; Drug or chemical Tissue Distribution; Drug resistance; Endocrine; Engineering; Estrogen Nuclear Receptor; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Estrogens; Female; Fulvestrant; Generations; Heat shock proteins; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Homing; Hormones; Lead; MCF7 cell; MDA MB 231; Mainstreaming; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Measures; Medical; Membrane; Molecular; Mus; Patients; Pharmaceutical Preparations; Population; Prevention; Problem Solving; Prodrugs; Property; Protein Isoforms; Proteins; Relapse; Research; Resistance; Resistance development; Selective Estrogen Receptor Modulators; Signal Transduction; Solid Neoplasm; Staging; Surface; T-Cell Lymphoma; Tamoxifen; Therapeutic Intervention; Toxic effect; Treatment outcome; Tumor Tissue; Up-Regulation; Vorinostat; Woman; Zolinza; antitumor agent; cancer therapy; cell motility; cell transformation; cohort; cytotoxic; cytotoxicity; design; falls; in vivo; malignant breast neoplasm; non-genomic; novel; oncology; public health relevance; receptor; receptor expression; success; therapeutic enzyme; therapeutic target; tumor; uptake

DESCRIPTION (provided by applicant): Breast cancer (BCa) ranks second only to lung cancer as the leading cause of US cancer deaths in women. A common mechanism for the sustenance of breast carcinoma is the malfunction of endocrine proteins such as estrogen receptor (ER). Therapeutic interventions that capitalize on such protein malfunction have enjoyed measured success in breast cancer therapy and/or chemo-prevention. For example, selective estrogen-receptor modulators (SERMs) such as tamoxifen are the first-line therapy for treatment of hormone dependent breast cancer. However, despite initial benefits, most patients eventually relapse due to acquired resistance to these drugs. The exact mechanisms of the acquired resistance are not completely understood. It is clear however that resistant tumors still maintain ER expression, either in the form of ER¿ (in more than 70% of the case) or up regulation of the expression of ER¿, a closely related isoform ER¿. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat the resistant stage BCa and early stage as well. The specific focus of the studies proposed in this application is to explore the tumor ER expression state to effect a selective delivery of an independent anti-tumor chemotype, in this case histone deacetylase inhibitor (HDACi). Our choice of HDAC as a therapeutic target is informed by the fact that HDAC inhibition is a clinically validated anti-cancr strategy that is selectively cytotoxic to transformed cells. HDACi continue to stimulate immense excitement in oncology, with close to 500 clinical trials initiated to date, thus far resulting in wo clinically approved drugs, SAHA (Zolinza") and FK228 (Istodax"), for the treatment of cutaneous T-cell lymphoma (CTCL). However, current HDACi have serious limitations resulting from poor biodistribution, including ineffectively low concentrations in solid tumors and off-target toxicity which is hampering clinical progress. The proposed research solves the problems of two mainstream cancer therapy agents - resistance development to estrogen-receptor modulators and lack of tumor accumulation of HDACi - to furnish a novel class targeted anti-BCa agents. If successful, the proposed research will lead to breakthroughs in BCa therapy and positively impact patients' treatment outcome.

描述（由适用提供）：乳腺癌（BCA）仅排名第二，仅是肺癌的主要原因，是美国癌症死亡的主要原因。维持乳腺癌的一种常见机制是内分泌蛋白（例如雌激素受体（ER））的故障。利用这种蛋白质故障的治疗性干预措施在乳腺癌治疗和/或预防性预防方面取得了成功。例如，选择性雌激素受体调节剂（SERM）（例如他氧法机）是治疗依赖马替酮乳腺癌的一线治疗。然而，多皮特初始益处，大多数患者最终由于对这些药物的耐药性而导致中继。获得的抗性的确切机制尚未完全理解。但是很明显，耐药性肿瘤仍然保持ER表达，要么以ER的形式（在70％的情况下）或对ER的表达的调节，这是密切相关的同工型ER？。因此，对越来越多的选择性和潜在药物的医学需求也需要治疗抗性阶段BCA和早期阶段。本应用中提出的研究的特定重点是探索肿瘤ER表达状态以选择性地递送独立的抗肿瘤化学型，在这种情况下，在这种情况下，组蛋白脱乙酰基酶抑制剂（HDACI）。我们选择将HDAC作为治疗靶标的，这是因为HDAC抑制是一种经过临床验证的抗癌症策略，它对转化的细胞有选择性地细胞毒性。 HDACI继续刺激肿瘤学的巨大兴奋，迄今为止启动了近500次临床试验，导致WO临床批准的药物Saha（Zolinza“）和FK228（Istodax”），用于治疗皮肤T细胞淋巴瘤（CTCL）。然而，当前的HDACI由于生物分布不良而产生的严重局限性，包括在实体瘤中无效的低浓度和脱靶毒性，这阻碍了临床进展。拟议的研究解决了两种主流癌症治疗剂的问题 - 抗雌激素受体调节剂的耐药性发展以及HDACI缺乏肿瘤的积累 - 提供了一种新型的靶向靶向抗BCA剂。如果成功，拟议的研究将导致BCA治疗的突破，并对患者的治疗结果产生积极影响。