Project 2: Optimizing Redox Modulation as a Therapeutic Strategy for NHL

项目 2：优化氧化还原调节作为 NHL 的治疗策略

• 批准号: 8381186
• 负责人: STEVEN H BERNSTEIN
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8381186
• 关键词: ATP-Dependent Proteases; Aftercare; Antioxidants; Apoptotic; Biological; Biological Markers; Cell Death; Cells; Clinic; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Data; Defense Mechanisms; Development; Diffuse; Diffuse Large-Cell Lymphoma; Drug Combinations; Drug Delivery Systems; Family; Generations; Goals; Histone Deacetylase Inhibitor; In Vitro; Laboratory Study; Lead; Learning; Lymphoma; Mantle Cell Lymphoma; Mediating; Mitochondria; Non-Hodgkin' s Lymphoma; Oxidation-Reduction; Oxidative Stress; Patients; Peptide Hydrolases; Phase; Proteasome Inhibitor; Proteins; Publishing; Reactive Oxygen Species; Refractory; Relapse; Research Design; Sampling; Schedule; System; Testing; Therapeutic; Thioredoxin; Xenograft Model; acivicin; base; cytotoxic; cytotoxicity; endopeptidase La; in vivo; inhibitor/antagonist; insight; interest; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; novel therapeutics; oleanane; pre-clinical; research clinical testing; tumor

Project 2: The triterpenoids are novel electrophilic compounds that we have shown induce apoptotic cell death in mantle cell lymphoma (MCL) and diffuse large cell lymphoma (DLCL). Indeed our published and preliminary studies suggest that these compounds manifest their cytotoxic effects by both increasing the generation of reactive oxygen species (ROS), and decreasing the activity of such critical anti-oxidant defense mechanisms as thioredoxin (Trx) and the mitochondria! proteases, Lon and CIpXP. This suggests a novel therapeutic strategy for lymphoma based on modulating the lymphoma cell redox state. In addition, our proposed mechanism suggests that other redox active agents, such as proteosome inhibitors and histone deacetylase inhibitors, are rationale agents to combine with the triterpenoids. The Specific Aims of this proposal have been developed to provide the essential pre-clinical data needed to support the clinical evaluation of the optimal triterpenoid and other redox active agent combinations for patients with DLCL and MCL. Specifically, in Specific Aim 1, we will validate our proposed mechanism of activity of the triterpenoids so to optimize triterpenoid drug combinations in vitro. These combinations will be further optimized and the biological targets of ROS generation, Trx and mitochondrial proteases validated in vivo using DLCL and MCL/SCID xenograft models in Specific Aim 2. We anticipate that the data derived from these Specific Aims will suggest an optimal triterpenoid combination, and sequence of drug delivery to be studied in the context of a phase l/ll trial as proposed in Specific Aim 3. A critical component of this trial will be the correlative laboratory studies whereby we propose to determine the in vivo effects of this drug combination on ROS, Trx and mitochondrial protease activity in patients with lymphoma. It is further anticipated that the lessons learned from these studies will support our long term goals which are to understand the clinical potential of the family of electrophilic compounds in NHL, which also includes the parthenolides, cucurmin, and the acivicins, and more importantly how best to exploit the redox state of lymphoma to generate new and effective approaches for the treatment of patients with NHL.

项目2： 三萜类化合物是我们显示的新型亲电化合物，诱导了凋亡细胞死亡 地幔细胞淋巴瘤（MCL）和弥漫性大细胞淋巴瘤（DLCL）。的确，我们发表的和初步的 研究表明，这些化合物通过增加产生来表现其细胞毒性作用 活性氧（ROS），并降低这种关键抗氧化剂防御机制的活性 如硫氧还蛋白（TRX）和线粒体！蛋白酶，LON和CIPXP。这暗示了一种新颖的治疗性 基于调节淋巴瘤细胞氧化还原态的淋巴瘤策略。此外，我们的建议 机制表明其他氧化还原活性剂，例如蛋白体抑制剂和组蛋白脱乙酰基酶 抑制剂是与三萜类化合物结合的基本原理。该提议的具体目的 已开发以提供支持支持临床评估所需的基本临床前数据 DLCL和MCL患者的最佳三萜和其他氧化还原活性剂组合。 具体而言，在特定的目标1中，我们将验证三萜的活性机理，以便 在体外优化三萜类药物组合。这些组合将得到进一步优化，并且 使用DLCL和 特定目标2中的MCL/SCID异种移植模型。我们预计从这些特定目的得出的数据 将提出最佳的三萜类化合物，并在此上下文中研究药物递送顺序 在特定目标3中提出的相位L/LL试验的相关性。该试验的关键组成部分将是相关性 实验室研究，我们建议确定该药物组合对ROS，TRX的体内影响 淋巴瘤患者的线粒体蛋白酶活性。进一步预期的是课程 从这些研究中学到的将支持我们的长期目标，这将了解 NHL中的亲电化合物家族，其中还包括par苯甲酰盐，库库明和 阿西维蛋白，更重要的是如何最好地利用淋巴瘤的氧化还原状态来产生新的和 有效治疗NHL患者的方法。