Pre-Clinical and Clinical Development of Silvestrol in Chronic Lymphocytic

西维甾醇治疗慢性淋巴细胞白血病的临床前和临床研究

基本信息

批准号：
7715179
负责人：
MICHAEL R GREVER
金额：
$ 26.92万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7715179
关键词：
Antineoplastic Agents Apoptosis Apoptotic Automobile Driving B lymphoid malignancy B-Cell Neoplasm B-Lymphocytes Biological Markers Caspase Cell Survival Cells Chemical Structure Chronic Chronic Lymphocytic Leukemia Clinical Clinical Trials Complement Data Development Developmental Therapeutics Program Disease Dose Drug Kinetics Effector Cell Family member Goals Half-Life Immune In Vitro Infection Instruction Investigation Lead Left Life Lymphocyte Lymphoma MCL1 protein Malignant Neoplasms Maximum Tolerated Dose Mediating Messenger RNA Modeling Mus Natural Products Chemistry Nature Ohio Opportunistic Infections Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology and Toxicology Pharmacy facility Phase Phase I Clinical Trials Phase II Clinical Trials Plants Production Property Proteins Refractory Relapse Relative (related person)Reliance Reproduction spores Research Risk Safety Screening procedure Staging System T-Lymphocyte TP53 gene Testing Therapeutic Translational Repression Translations Universities Validation Work adult leukemia base clinical efficacy college cytotoxicity drug development fighting flavopiridol improved in vivo inhibitor/antagonist killings leukemia mTOR Inhibitor mouse model nanoparticle neoplastic cell novel pre-clinical preclinical study silvestrol small molecule libraries

项目摘要

Chronic lymphocytic leukemia (CLL) is an incurable type of B-cell leukemia. Identifying novel agents that target molecules crucial to CLL cell survival represents a powerful therapeutic strategy for this disease. The anti-apoptotic protein Mcl-1 is one such target in CLL. Reduction of Mcl-1 promotes apoptosis and enhances the efficacy of other CLL therapies. We demonstrated that the novel plant-derived agent silvestrol down-regulates Mcl-1 expression through a translation-mediated mechanism in CLL cells, with subsequent apoptosis. Silvestrol is effective against CLL cells with p53 deletions, and lacks the cellular immune suppression associated with other currently available CLL therapies. As a consequence of our work to date, silvestrol was recently selected for full preclinical development by the NCI Developmental Therapeutics Program Drug Development Group at the Stage IIA level. The research proposed here will complement the NCI preclinical work by conducting crucial mechanistic and translational investigations of silvestrol, and ultimately, a Phase I clinical trial in refractory CLL. The driving hypothesis of this investigation is that silvestrol mediates potent cytotoxicity against CLL cells via translational inhibition of the Mcl-1 protein and will represent an effective and well-tolerated therapy for CLL patients. To pursue this hypothesis, we have proposed four aims: Aim 1 is to determine the precise mechanism of silvestrol-mediated translational inhibition and subsequent apoptosis in CLL cells. Aim 2 includes pre-clinical in vitro and in vivo studies with silvestrol in CLL cells and murine leukemia models to identify rational combination strategies with known agents. Aim 3 will develop strategies to further enhance tumor cell exposure and in vivo efficacy of silvestrol through the use of silvestrol-loaded nanoparticles. In Aim 4, we will pursue a Phase I clinical trial to assess silvestrol safety, maximum tolerated dose, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy in patients with relapsed, refractory CLL. Using these approaches and working in concert with the NCI efforts, the proposed research will greatly accelerate the development of silvestrol for clinical use in CLL and other B-cell malignancies. RELEVANCE (See instructions): The incurable disease B-cell chronic lymphocytic leukemia (CLL) presents 15,000+ new cases annually in the US. CLL results in profound immune suppression with subsequent risk of lethal opportunistic infections. Available treatments that kill B tumor cells also kill infection-fighting T cells, leaving patients at further risk. Silvestrol effectively and selectively kills B cells relative to T cells, using a mechanism unlike any drug now available for CLL. Thus, clinical use of silvestrol could potentially improve survival and reduce infections. Such an agent is also likely to be effective in other B cell cancers including lymphomas.

慢性淋巴细胞白血病 (CLL) 是一种无法治愈的 B 细胞白血病。识别新的代理对 CLL 细胞存活至关重要的靶分子代表了该疾病的强大治疗策略。抗凋亡蛋白 Mcl-1 就是 CLL 中的此类靶标之一。 Mcl-1 的减少促进细胞凋亡增强其他 CLL 疗法的疗效。我们证明了新型植物源制剂 silvestrol 通过翻译介导的机制下调 CLL 细胞中 Mcl-1 的表达，随后发生细胞凋亡。 Silvestrol 对 p53 缺失的 CLL 细胞有效，并且缺乏细胞与其他目前可用的 CLL 疗法相关的免疫抑制。作为我们的结果迄今为止的工作，silvestrol 最近被 NCI Developmental 选择进行全面的临床前开发 IIA 阶段治疗计划药物开发小组。这里提出的研究将通过进行重要的机制和转化研究来补充 NCI 的临床前工作 silvestrol，最终是难治性 CLL 的 I 期临床试验。这一假设的驱动假设研究表明西维甾醇通过翻译抑制来介导针对 CLL 细胞的有效细胞毒性 Mcl-1 蛋白将成为 CLL 患者有效且耐受性良好的疗法。为了追求这个假设，我们提出了四个目标：目标 1 是确定西维甾醇介导的翻译抑制的精确机制以及随后的 CLL 细胞凋亡。目标 2 包括在 CLL 细胞中使用西维甾醇进行临床前体外和体内研究和小鼠白血病模型，以确定与已知药物的合理组合策略。目标3将制定策略，通过使用进一步增强西维甾醇的肿瘤细胞暴露和体内功效负载西维酚的纳米颗粒。在目标 4 中，我们将进行 I 期临床试验来评估 silvestrol 安全性、最大耐受剂量、药代动力学和药效学特性以及初步对复发、难治性 CLL 患者的疗效。使用这些方法并与 NCI 的努力协同工作，拟议的研究将极大地促进加速用于 CLL 和其他 B 细胞恶性肿瘤临床应用的西维甾醇的开发。相关性（参见说明）：不治之症 B 细胞慢性淋巴细胞白血病 (CLL) 每年在中国出现 15,000 多例新病例美国。 CLL 会导致严重的免疫抑制，从而带来致命的机会性感染的风险。现有的杀死 B 肿瘤细胞的治疗方法也会杀死抗感染的 T 细胞，使患者面临进一步的风险。 Silvestrol 可有效且选择性地杀死 B 细胞（相对于 T 细胞），其机制与目前任何药物都不同可用于 CLL。因此，西尔维甾醇的临床使用可能会提高生存率并减少感染。这种药物也可能对包括淋巴瘤在内的其他 B 细胞癌症有效。