Translational Studies of the Histone Deacetylase Inhibitor Romidepsin

组蛋白脱乙酰酶抑制剂罗米地辛的转化研究

• 批准号: 7965470
• 负责人: susan bates
• 金额: $ 81.59万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965470
• 关键词: ABCB1 gene; Acetylation; Advisory Committees; Area; Area Under Curve; Australia; Award; Biological Assay; Biological Markers; Blinded; Blood; California; Cancer Center; Cancer Therapy Evaluation Program; Cardiac; Cardiology; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Cities; Clinic; Clinical; Clinical Research; Clinical Trials; Coin; Combined Modality Therapy; Complement; Continuous Infusion; Critical Pathways; Cutaneous; Cytoplasmic Protein; Data; Defect; Depsipeptides; Development; Disease; Disease Progression; Disease remission; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Electrocardiogram; Ensure; Etoposide; Experimental Models; Exposure to; Extramural Activities; Gene Expression; Generations; Genes; Histology; Histone Acetylation; Histone Deacetylase Inhibitor; IL2RA gene; Image; Immunoblotting; In complete remission; Investigation; Laboratories; Licensing; Life; Malignant Neoplasms; Malignant neoplasm of thyroid; Manuscripts; Mediating; Medical Oncology; Mitotic; Monitor; Mononuclear; Multi-Drug Resistance; Multi-Institutional Clinical Trial; Myocardial; New York; Orphan Drugs; Partial Remission; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Preparation; Principal Investigator; Radioactive Iodine; Rare Diseases; Regulation; Relative (related person); Reporting; Research; Research Personnel; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rights; Safety; Sampling; Schedule; Site; Social Welfare; Study Subject; T-Cell Lymphoma; Therapeutic; Time; Troponin; University Hospitals; Work; advanced disease; angiogenesis; anticancer research; base; chemotherapy; cohort; human study; human subject protection; interest; lung small cell carcinoma; meetings; millisecond; oncology; phrases; pre-clinical; prevent; programs; research study; resistance mechanism; response; symporter; therapy development; translational study; tumor; uptake

We have studied the histone deacetylase inhibitor depsipeptide (now known as romidepsin) in both the clinic and in the laboratory. We originally became interested in depsipeptide in the context of a clinical trial strategy seeking to identify agents that could overcome or circumvent multidrug resistance. My laboratory identified the histone deacetylase inhibitor depsipeptide as an agent in preclinical development and a substrate for Pgp-mediated efflux. Because depsipeptide is avidly transported by Pgp, and because it induces MDR-1 in the constellation of genes altered by histone acetylation, we planned to eventually develop depsipeptide in combination with a Pgp modulator. However, in the Phase I setting, we made the serendipitous discovery that depsipeptide was highly effective in subsets of T cell lymphoma. While we have continued to be interested in our original strategy of preventing the emergence of resistance to this agent, we have pursued the use of depsipeptide/romidepsin as an orphan drug in T cell lymphoma, using both laboratory and clinical strategies. Futhermore, our biomarker data do not suggest that Pgp develops as a mechanism of drug resistance following exposure to this compound. Our multi-institutional clinical trial for cutaneous and peripheral T cell lymphoma (CTCL and PTCL) has completed accrual at 140 patients in 6 cohorts. Cohort 1, patients with cutaneous T cell lymphoma with fewer than 2 systemic chemotherapy regimens, is complete and a manuscript is in preparation. The responses to depsipeptide are at times dramatic and have been very durable. As an example, one patient received therapy continuously for over 6 years, remained in a partial remission off of therapy for 20 months and has now resumed therapy for CTCL. Another patient with CTCL remains in complete remission off of therapy for over 3 years, and another patient with PTCL remains in continuous complete remission. We have anecdotally coined the phrase "there when you need it" for romidepsin, based on its activity in retreating patients who demonstrate disease progression while off of therapy. The major response rate for depsipeptide, now termed romidepsin, in cutaneous T cell lymphoma in both our NCI trial and in the Gloucester registration trial is 34-35%. It is important to note that durable responses were also obtained by extramural investigators who were participating in our Phase II trial among more than 9 multicenter sites included in the study. These sites included North Shore University Hospital in Manhasset, New York; City of Hope National Cancer Center in Duarte, California; and Peter MacCallum Cancer Center in Melbourne, Australia. Gloucester Pharmaceuticals obtained Orphan Drug status from the FDA for development of this therapy for CTCL. A Gloucester registration trial demonstrated responses comparable to those observed on our trial. NCI CTEP and our Cancer Therapeutics Branch (now Medical Oncology Branch) largely pushed the development of this agent alone during a period in which Fujisawa Pharmaceuticals debated the relative merits of becoming involved in an oncology development platform. Responses with PTCL are also durable and Gloucester has developed a registration strategy for that indication as well. A registration-directed Phase II clinical trial in PTCL has been launched by the company, with Dr. Richard Piekarz as principal investigator at our site. Our NCI Phase II trial had a major second objective in addition to proving efficacy in the various histologies. That is confirmation of the safety of the agent. EKG abnormalities have been noted following treatment and a great deal of effort has gone into demonstrating the lack of myocardial damage associated with administration of this agent. We reported in June of 2006 in Clinical Cancer Research, our review of 2,051 ECGs obtained in 42 patients treated with depsipeptide. These ECGs demonstrate the previously documented reversible ST and T wave changes in the majority of patients, unassociated with any abnormality in cardiac function or change in troponin level. In addition, a median increase in the corrected QT interval of 14 msec. This increase is based on the Bazett correction. When a blinded cardiology review conducted as part of the NDA submission was performed on over 4000 ECGs using the Fridericia correction, it was concluded that the median increase was between 2 and 5 msec. The trial has a significant translational component that has consumed a major fraction of my laboratory resources. We have developed a quantitative immunoblot assay for detecting and quantitating histone acetylation in patient samples, principally peripheral mononuclear cells as a surrogate. Results from these assays have been compared to pharmacokinetic data. We have also evaluated gene expression including CD25, p21, and MDR1 by RT-PCR, finding that only MDR1 expression is induced sufficiently following depsipeptide for routine assay in patient mononuclear cells. MDR1 is also analyzed in tumor samples before therapy is initiated and then at the time of disease progression. Our data suggest that the 24hr timepoint of histone acetylation in peripheal blood mononuclear cells is associated with pharmacokinetic parameters including clearance and area under the curve. In addition, our data suggest that this endpoint is assocated with disease response. Taken together these data suggest that drug exposure may be important for romidepsin and potentially for the entire class of histone deacetylase inhibitors. Additional studies include a Phase I trial of romidepsin on a day 1, 3, and 5 schedule to achieve a more continuous drug effect. Dr. Richard Piekarz is PI on this study. This study has a focus in thyroid cancer, evaluating radioactive iodine uptake, which was observed in experimental models. The Phase I trial is ongoing, with samples collected for pharmacokinetic and pharmacodynamic analysis. In patients with thyroid cancer (one patient per dose level and then expanding at the MTD), radioiodine imaging performed, hoping that induction of the Na+/I- symporter at the cellular level will enhance radioiodine uptake. We have a new clinical trial of an histone deacetylase inhibitor ongoing, evaluating 48 hr continuous infusion belinostat in combination with cisplatin and etoposide. This trial is based on preclinical evidence of synergy between HDAC inhibitors and chemotherapeutics, when properly scheduled. This will be carried out as a Phase I trial in an advanced disease population and then as a Phase II trial in small cell lung cancer. Finally, we have been interested for some time in mechanisms of depsipeptide sensitivity and resistance. This led us to the generation of cell lines with non-Pgp mediated depsipeptide resistance and we have begun to ask whether other mechanisms of resistance can be identified. Preliminary studies suggest that there is a drug accumulation defect in these cells and a mechanism underlying that is being sought. We continue to be interested in the mechanism of action of depsipeptide. At least 5 mechanisms have been cited for histone deacetylase inhibitors: induction of gene expression, acetylation of cytoplasmic proteins and altered function, increased degradation of cytoplasmic proteins due to impaired Hsp90 activity, altered angiogenesis, and mitotic effects. Exactly which mechanism is of critical importance will be the subject of continuing investigation. These studies have also been complemented by experiments aimed at identifying synergistic drug combinati [summary truncated at 7800 characters]

我们在临床和实验室研究了组蛋白脱乙酰酶抑制剂 depsipeptide（现称为 romidepsin）。我们最初对缩酚肽感兴趣是在临床试验策略的背景下，旨在寻找能够克服或规避多药耐药性的药物。我的实验室鉴定出组蛋白脱乙酰酶抑制剂缩酚肽是临床前开发中的一种药物，也是 Pgp 介导的外排的底物。由于缩酚肽是由 Pgp 强烈转运的，而且它会在组蛋白乙酰化改变的基因群中诱导 MDR-1，因此我们计划最终开发缩酚肽与 Pgp 调节剂的组合。然而，在 I 期临床试验中，我们偶然发现缩酚肽对 T 细胞淋巴瘤亚型非常有效。 虽然我们仍然对防止这种药物出现耐药性的最初策略感兴趣，但我们已经利用实验室和临床策略，将缩肽/罗米地辛作为 T 细胞淋巴瘤的孤儿药。此外，我们的生物标志物数据并不表明 Pgp 在接触该化合物后会发展为耐药机制。我们针对皮肤和外周 T 细胞淋巴瘤（CTCL 和 PTCL）的多机构临床试验已完成 6 个队列的 140 名患者的招募。第 1 组是接受少于 2 种全身化疗方案的皮肤 T 细胞淋巴瘤患者，该组已完成，正在准备手稿。对缩酚肽的反应有时非常剧烈并且非常持久。例如，一名患者连续接受治疗超过 6 年，治疗结束后 20 个月保持部分缓解，现已恢复 CTCL 治疗。另一名 CTCL 患者在治疗后仍保持完全缓解超过 3 年，另一名 PTCL 患者仍保持持续完全缓解。有趣的是，我们为罗米地辛创造了“当你需要它时就出现”这个短语，这是基于它在停药期间表现出疾病进展的复发患者中的活性。在我们的 NCI 试验和格洛斯特注册试验中，缩酚肽（现称为罗米地辛）治疗皮肤 T 细胞淋巴瘤的主要缓解率为 34-35%。值得注意的是，参与我们研究中超过 9 个多中心站点的 II 期试验的外部研究人员也获得了持久的反应。这些地点包括纽约州曼哈塞特的北岸大学医院；位于加利福尼亚州杜阿尔特的希望之城国家癌症中心；和澳大利亚墨尔本的彼得麦卡勒姆癌症中心。格罗斯特制药公司因开发这种 CTCL 疗法而获得 FDA 的孤儿药资格。格洛斯特注册试验显示的反应与我们试验中观察到的反应相当。在 Fujisawa Pharmaceuticals 争论参与肿瘤开发平台的相对优点期间，NCI CTEP 和我们的癌症治疗分部（现为肿瘤内科分部）在很大程度上单独推动了该药物的开发。 PTCL 的反应也很持久，格洛斯特也针对该适应症制定了注册策略。该公司已启动 PTCL 的注册导向的 II 期临床试验，Richard Piekarz 博士担任我们网站的首席研究员。除了证明各种组织学的有效性之外，我们的 NCI II 期试验还有第二个主要目标。这是对代理人安全性的确认。 治疗后已注意到心电图异常，并且已付出大量努力来证明与使用该药物相关的心肌损伤的存在。我们于 2006 年 6 月在《临床癌症研究》中报道了我们对 42 名接受缩酚肽治疗的患者获得的 2,051 份心电图进行的审查。这些心电图显示了先前记录的大多数患者的可逆 ST 和 T 波变化，与心功能异常或肌钙蛋白水平变化无关。此外，校正后的 QT 间期中值增加了 14 毫秒。这一增长是基于 Bazett 修正。当作为 NDA 提交的一部分进行盲法心脏病学审查时，使用 Fridericia 校正对 4000 多个心电图进行，得出的结论是中位增加在 2 到 5 毫秒之间。该试验有一个重要的转化部分，消耗了我实验室的大部分资源。我们开发了一种定量免疫印迹测定法，用于检测和定量患者样本中的组蛋白乙酰化，主要是作为替代的外周单核细胞。这些测定的结果已与药代动力学数据进行了比较。我们还通过 RT-PCR 评估了包括 CD25、p21 和 MDR1 在内的基因表达，发现在患者单核细胞中使用缩酚肽进行常规检测后，仅充分诱导 MDR1 表达。还在开始治疗之前和疾病进展时对肿瘤样本中的 MDR1 进行分析。我们的数据表明，外周血单核细胞中组蛋白乙酰化的 24 小时时间点与药代动力学参数（包括清除率和曲线下面积）相关。此外，我们的数据表明该终点与疾病反应相关。总而言之，这些数据表明药物暴露可能对罗米地辛很重要，并且可能对整个组蛋白脱乙酰酶抑制剂类都很重要。其他研究包括按第 1 天、第 3 天和第 5 天进行的罗米地辛 I 期试验，以实现更持续的药物作用。 Richard Piekarz 博士是这项研究的 PI。这项研究的重点是甲状腺癌，评估在实验模型中观察到的放射性碘摄取。 I 期试验正在进行中，收集样本用于药代动力学和药效学分析。在甲状腺癌患者中（每个剂量水平一名患者，然后在 MTD 扩展），进行了放射性碘成像，希望在细胞水平上诱导 Na+/I- 同向转运蛋白将增强放射性碘的摄取。我们正在进行一项组蛋白脱乙酰酶抑制剂的新临床试验，评估 48 小时连续输注贝利司他与顺铂和依托泊苷的组合。 该试验基于 HDAC 抑制剂和化疗药物在适当安排的情况下具有协同作用的临床前证据。这将作为晚期疾病人群的 I 期试验进行，然后作为小细胞肺癌的 II 期试验进行。最后，我们对缩酚肽敏感性和耐药性的机制感兴趣已有一段时间了。这导致我们产生了具有非 Pgp 介导的缩酚肽抗性的细胞系，并且我们已经开始询问是否可以识别其他抗性机制。 初步研究表明这些细胞中存在药物蓄积缺陷，并且正在寻找其潜在机制。我们仍然对缩酚肽的作用机制感兴趣。组蛋白脱乙酰酶抑制剂至少有 5 种机制：诱导基因表达、细胞质蛋白乙酰化和功能改变、Hsp90 活性受损导致细胞质蛋白降解增加、血管生成改变和有丝分裂效应。究竟哪种机制至关重要将是持续调查的主题。这些研究还得到了旨在确定协同药物组合的实验的补充[摘要被截断为 7800 个字符]