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: 8552751
• 负责人: susan bates
• 金额: $ 83.7万
• 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/8552751
• 关键词: ABCB1 gene; Acetylation; Animals; Area Under Curve; Australia; Biological Assay; Biological Markers; Blood; California; Cancer Center; Cancer Patient; Cardiac; Cell Line; Cells; Cisplatin; Cities; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Complement; Continuous Infusion; Critical Pathways; Cutaneous; Cytoplasmic Protein; Data; Depsipeptides; Disease; Disease remission; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Electrocardiogram; Electrolytes; Etoposide; Experimental Models; Extramural Activities; FDA approved; Gene Expression; Generations; Goals; Histology; Histone Acetylation; Histone Deacetylase Inhibitor; Hydroxamic Acids; IL2RA gene; Immunoblotting; In complete remission; Investigation; Laboratories; Laboratory Study; Licensing; Life; Lymphoma; Malignant neoplasm of thyroid; Mediating; Mitotic; Mononuclear; Multi-Institutional Clinical Trial; Myocardial; Names; New York; Orphan Drugs; Paper; Partial Remission; Patients; Pennsylvania; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Protocols documentation; Publications; Publishing; Radioactive Iodine; Rare Diseases; Relapse; Reporting; Research Personnel; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Safety; Sampling; Schedule; Site; Solid Neoplasm; Supplementation; T-Cell Lymphoma; Time; Translating; Universities; University Hospitals; Work; advanced disease; angiogenesis; base; cDNA Arrays; chemotherapy; cohort; improved; interest; lung small cell carcinoma; novel; patient population; phase 1 study; pre-clinical; prevent; research study; resistance mechanism; response; translational study; tumor; uptake

We have studied the histone deacetylase inhibitors romidepsin and belinostat in both the clinic and in the laboratory. We originally became interested in romidepsin in the context of a Phase I clinical trial, when we made the serendipitous discovery that (then-named) 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 first pursued the use of depsipeptide/romidepsin as an orphan drug in T cell lymphoma, using both laboratory and clinical strategies. We have extended this work into solid tumors with the hydroxamic acid derivative belinostat.Our multi-institutional clinical trial for cutaneous and peripheral T cell lymphoma (CTCL and PTCL) completed accrual at 131 patients in 6 cohorts. Papers detailing responses to romidepsin in both CTCL and PTCL are published. 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 7 years, and another patient with PTCL remained in continuous complete remission for 5 years before relapse occurred. The major response rate in cutaneous T cell lymphoma in both our NCI trial and in the Gloucester registration trial was 34-35%. For PTCL, our response rate was 38%. It is important to note that durable responses were also obtained in both subsets of patients 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.Our NCI Phase II trial had a major second objective in addition to proving efficacy in the various histologies. That was 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 have analyzed over 4000 ECGs, and collected much ancillary cardiac safety data. A goal in the coming year is to report additional cardiac findings with romidepsin that help establish the safety of the agent, and parameters for using all HDIs in conjunction with electrolyte supplementation. The trial had a significant translational component that consumed a major fraction of my laboratory resources. We 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 were 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. 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 associated 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. I addition, samples were sent as per protocol to Dr. Louise Showe at University of Pennsylvania. These samples have been analyzed by cDNA array and the data are being prepared for publication.Additional studies included a Phase I trial of romidepsin on a day 1, 3, and 5 schedule to achieve a more continuous drug effect. Dr. Richard Piekarz was PI on this study. This study had a focus in thyroid cancer, evaluating radioactive iodine uptake, which was observed in experimental models. The Phase I trial was completed; our assessment was that the dose and schedule did not give optimal gene expression changes. The question of how best to increase radioiodine accumulation in thyroid cancer remains an important one.We have nearly completed a combination clinical trial with a novel histone deacetylase inhibitor, belinostat, evaluating a 48 hr continuous infusion in combination with cisplatin and etoposide. This trial is based on preclinical evidence of synergy between HDAC inhibitors and chemotherapeutics, when properly scheduled. This was carried out as a Phase I trial in an advanced disease population; we are currently refining a Phase II dose. The Phase II dose will be explored in the same trial design in the small cell lung cancer patient population. Laboratory studies supporting the clinical trial have been published this year.Finally, we have been interested for some time in mechanisms of HDI sensitivity and resistance. This led us to the generation of cell lines with non-Pgp mediated romidepsin resistance and we have begun to ask whether other mechanisms of resistance can be identified. We continue to be interested in the mechanism of action of the HDIs. 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 combinations. We have identified a two drug combination that has markedly increased the activity already observed in monotherapy in lymphoma and we hope will translate into activity in solid tumors. Animal studies supporting a protocol concept for the combination of romidepsin with an experimental agent are ongoing; we plan to open a Phase I study of this combination in the coming year.

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romidepsin和belinostat。我们最初在I期临床试验的背景下对romidepsin产生了兴趣，当我们提出偶然发现（当时为命名的）Depspeptide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耐药性出现的最初策略感兴趣，但我们首先使用实验室和临床策略，在T细胞淋巴瘤中使用Depspypeptide/Romidepsin作为T细胞淋巴瘤中的孤儿药。我们已经将这项工作扩展到了羟酸性衍生物Belinostat中。我们针对皮肤和周围T细胞淋巴瘤（CTCL和PTCL）的多机构临床试验完成了131例患者的应计。 在CTCL和PTCL中详细介绍了对romidepsin的反应的论文。 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7年以上一直处于完全缓解治疗中，而另一位PTCL患者在复发之前仍保持连续完全缓解5年。在我们的NCI试验和格洛斯特登记试验中，皮肤T细胞淋巴瘤的主要反应率为34-35％。对于PTCL，我们的回应率为38％。重要的是要注意，在研究中包括9个以上的多中心地点中，他们参加了我们参加我们II期试验的两种患者子集中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；以及澳大利亚墨尔本市的彼得·麦卡勒姆（Peter MacCallum）癌症中心。除了证明在各种组织学中的功效外，我们的NCI II期试验还具有重大的第二个目标。 那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。我们已经分析了4000多个心电图，并收集了许多辅助心脏安全数据。 来年的一个目标是通过romidepsin报告其他心脏发现，该发现有助于确定代理的安全性，以及与补充电解质的所有HDI一起使用所有HDI的参数。该试验具有重要的翻译成分，可以消耗我的实验室资源的很大一部分。 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品中的组蛋白乙酰化，主要是外周单核细胞作为替代物。 将这些测定的结果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。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有关。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。我补充，根据协议将样品发送给宾夕法尼亚大学的路易丝·夏（Louise Showe）博士。这些样品已经通过cDNA阵列进行了分析，并准备了数据以进行出版。 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，评估了放射性碘摄取，这在实验模型中观察到。 第一阶段的试验完成了；我们的评估是剂量和时间表没有给出最佳的基因表达变化。如何最好地增加甲状腺癌的放射性碘积累的问题仍然是一个重要的问题。我们几乎完成了一项新型组蛋白脱乙酰基酶抑制剂Belinostat的组合临床试验，评估了与顺铂和依托昔替肽结合的48小时连续输注。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。这是在晚期疾病人群中作为I期试验进行的；我们目前正在完善II期剂量。在小细胞肺癌患者人群中，将在同一试验设计中探索II期剂量。支持临床试验的实验室研究已于今年发表。在最后，我们对HDI敏感性和耐药性的机制感兴趣。这导致我们产生了具有非PGP介导的romidepsin耐药性的细胞系，我们已经开始询问是否可以鉴定出其他耐药机制。 我们继续对HDI的作用机理感兴趣。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。这些研究也通过旨在鉴定协同药物组合的实验补充。我们已经确定了一种两种药物组合，显着增加了淋巴瘤单药治疗中已经观察到的活性，我们希望能够转化为实体瘤的活性。动物研究支持协议概念，将romidepsin与实验剂结合在一起；我们计划在来年对这一组合进行I阶段研究。