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]

我们已经研究了诊所和实验室中的组蛋白脱乙酰基酶抑制剂抑制剂（现在称为romidepsin）。我们最初在临床试验策略的背景下对二肽感兴趣，该策略寻求识别可以克服或规避多药耐药性的药物。我的实验室确定组蛋白脱乙酰基酶抑制剂Depspeptide是临床前发育中的药物和PGP介导的外排的底物。由于二肽是通过PGP大量运输的，并且由于组蛋白乙酰化改变了基因的星座，因此我们计划最终与PGP调节剂结合使用Depsipeptide。但是，在第一阶段的设置中，我们提出了偶然发现的发现，即深肽在T细胞淋巴瘤的亚群中非常有效。 尽管我们继续对防止对该药物的抗性出现的最初策略感兴趣，但我们采用了使用实验室和临床策略的二肽/romidepsin作为T细胞淋巴瘤中的孤儿药。 futhermore，我们的生物标志物数据并不建议PGP在暴露于​​该化合物后发展为耐药性的机制。我们针对皮肤和周围T细胞淋巴瘤（CTCL和PTCL）的多机构临床试验已完成60名同龄人的140例患者的应计。队列1，皮肤T细胞淋巴瘤患者的患者少于2个全身化疗方案，并且正在制备手稿。对深肽的反应有时是戏剧性的，并且非常耐用。例如，一名患者连续接受治疗超过6年，在治疗中保留了20个月的部分缓解，现在已经恢复了CTCL治疗。另一位CTCL患者在3年以上仍处于完全缓解治疗中，另一位PTCL患者仍处于持续的完全缓解状态。基于其在撤回治疗过程中证明疾病进展的患者方面的活性，我们轶事地为Romidepsin创造了“当您需要时”一词。在我们的NCI试验和格洛斯特登记试验中，皮肤T细胞淋巴瘤中的二肽的主要缓解率均为34-35％。重要的是要注意，在研究中包括9多个多中心地点的II期试验的外壁外研究人员也获得了持久的反应。这些地点包括纽约曼哈塞特的北岸大学医院；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Peter MacCallum癌症中心。 Gloucester Pharmaceuticals从FDA获得了孤儿药物，用于开发CTCL疗法。格洛斯特登记试验显示的反应与我们试验中观察到的反应相当。 NCI CTEP和我们的癌症治疗分支（现为医学肿瘤学分支机构）在很大程度上推动了该药物的开发，在富士岛制药公司对参与肿瘤学发展平台的相对优点进行了辩论。对PTCL的响应也很耐用，格洛斯特也为该指示制定了注册策略。该公司已与Richard Piekarz博士担任我们网站的首席研究员，在PTCL进行了注册指导的II期临床试验。我们的NCI II期试验除了证明在各种组织学中的功效外，还具有重大的第二个目标。这是对代理商安全的确认。 治疗后已经注意到了心电图异常，并且已经大力证明与该药物的给药相关的心肌损害缺乏。我们在2006年6月在临床癌症研究中报道了我们对42例接受Depspeptide治疗的患者获得的2,051个ECG的评论。这些心电图证明了大多数患者的先前记录的可逆ST和T波变化，与心脏功能异常或肌钙蛋白水平的变化无关。另外，校正QT间隔的中位数增加为14毫秒。这种增加是基于Bazett校正的。当使用Fridericia校正对4000多个ECG进行了作为NDA提交的一部分进行的盲人心脏病学审查时，得出的结论是，中位数增加在2至5毫秒之间。该试验具有重要的翻译组成部分，它消耗了我的实验室资源的很大一部分。我们已经开发了一种定量免疫印迹测定法，用于检测和定量患者样品中的组蛋白乙酰化，这主要是外周单核细胞作为替代物。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，发现只有MDR1表达才能充分诱导后二肽，以便在患者单核细胞中进行常规测定。在开始治疗之前，然后在疾病进展时，还会在肿瘤样品中分析MDR1。我们的数据表明，周围血液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有关，包括清除率和曲线下的面积。此外，我们的数据表明该终点与疾病反应相关。综上所述，这些数据表明，药物暴露对romidepsin可能很重要，对于整个组蛋白脱乙酰基酶抑制剂可能很重要。其他研究包括在第1、3和第5天的I阶段试验，以实现更连续的药物效应。理查德·皮卡尔斯（Richard Piekarz）博士是这项研究的PI。这项研究的重点是甲状腺癌，评估放射性碘摄取，这在实验模型中观察到。 I期试验正在进行中，并收集了用于药代动力学和药效分析的样品。在甲状腺癌患者（每剂量水平为一名患者，然后在MTD处膨胀），放射性二世成像进行了，希望在细胞水平上诱导Na+/I-共旋转菌诱导能够增强放射性碘的摄取。我们进行了一项新的临床试验，对正在进行的组蛋白脱乙酰基酶抑制剂，评估48小时连续输注Belinostat与顺铂和依托泊苷结合使用。 该试验基于适当安排的HDAC抑制剂和化学治疗剂之间协同作用的临床前证据。这将在晚期疾病人群中作为I期试验进行，然后作为小细胞肺癌的II期试验进行。最后，我们对二肽敏感性和抗性的机制感兴趣。这导致我们产生了具有非PGP介导的二肽耐药性的细胞系，我们已经开始询问是否可以鉴定出其他抗性机制。 初步研究表明，这些细胞中存在药物积累缺陷以及正在寻求的机制。我们继续对二肽作用机理感兴趣。已经引用了组蛋白脱乙酰基酶抑制剂的至少5种机制：诱导基因表达，细胞质蛋白的乙酰化和功能的改变，由于影响HSP90活性的胞质蛋白的降解增加，血管生成的改变，血管生成的改变以及促丝效应。哪种机制至关重要，将是继续调查的主题。这些研究也得到了旨在识别协同药物组合的实验[摘要以7800个字符的截断]