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

• 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
• 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

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）是一种不可治愈的B细胞白血病。确定新的代理人， 对CLL细胞存活至关重要的靶向分子代表了这种疾病的强有力的治疗策略。 抗凋亡蛋白Mcl-1是CLL中的一个这样的靶标。Mcl-1的减少促进细胞凋亡， 增强其他CLL疗法的疗效。我们证明了新的植物源性药物 在CLL细胞中，司维司群通过抑制介导的机制下调Mcl-1表达， 随后的凋亡。Silvestrol对p53缺失的CLL细胞有效， 与其他目前可用的CLL疗法相关的免疫抑制。由于我们的 到目前为止，Silvestrol最近被NCI Developmental选中进行全面的临床前开发 IIA期水平的治疗学项目药物开发组。本文提出的研究将 通过进行关键的机制和翻译研究来补充NCI的临床前工作， 西司特罗，最终，难治性CLL的I期临床试验。这个驱动假设 研究表明，司维司群通过翻译抑制 Mcl-1蛋白，并将代表CLL患者的有效且耐受良好的疗法。追求这个 假设，我们提出了四个目标： 目的1是确定西司特罗介导的翻译抑制的确切机制， CLL细胞凋亡。目的2包括在CLL细胞中进行的临床前体外和体内研究 和鼠白血病模型来鉴定与已知药剂的合理组合策略。目标3将 开发策略，通过使用 载司维司群的纳米颗粒。在目标4中，我们将进行I期临床试验， 安全性、最大耐受剂量、药代动力学和药效学特性以及初步 复发性、难治性CLL患者的疗效。 使用这些方法并与NCI的努力相配合，拟议的研究将大大 加速开发用于CLL和其他B细胞恶性肿瘤临床应用的司维司群。 相关性（参见说明）： 无法治愈的疾病B细胞慢性淋巴细胞白血病（CLL）每年有15，000多例新病例， 美方CLL导致严重的免疫抑制，随后有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，使患者面临更大的风险。 Silvestrol有效地和选择性地杀死相对于T细胞的B细胞，使用一种不同于现在任何药物的机制 可用于CLL。因此，临床使用司维司群有可能提高生存率并减少感染。 这种药物也可能对其他B细胞癌症包括淋巴瘤有效。