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

项目2： 三萜类化合物是新型亲电子化合物，我们已证明其可诱导细胞凋亡 套细胞淋巴瘤（MCL）和弥漫性大细胞淋巴瘤（DLCL）。事实上，我们已发布和初步 研究表明，这些化合物通过增加细胞的产生来表现出细胞毒性作用。 活性氧（ROS），并降低此类关键抗氧化防御机制的活性 作为硫氧还蛋白（Trx）和线粒体！蛋白酶、Lon 和 CIpXP。这提出了一种新的治疗方法 基于调节淋巴瘤细胞氧化还原状态的淋巴瘤策略。此外，我们建议 机制表明其他氧化还原活性剂，例如蛋白酶体抑制剂和组蛋白脱乙酰酶 抑制剂，是与三萜类化合物结合的基本药物。该提案的具体目标有 旨在提供支持临床评估所需的基本临床前数据 DLCL 和 MCL 患者的最佳三萜类化合物和其他氧化还原活性剂组合。 具体来说，在具体目标 1 中，我们将验证我们提出的三萜类化合物的活性机制，以便 体外优化三萜类药物组合。这些组合将进一步优化 使用 DLCL 在体内验证 ROS 生成、Trx 和线粒体蛋白酶的生物靶标 具体目标 2 中的 MCL/SCID 异种移植模型。我们预计源自这些具体目标的数据 将建议最佳的三萜类化合物组合，以及要在上下文中研究的药物输送顺序 具体目标 3 中提出的 l/ll 期试验。该试验的一个关键组成部分是相关的 我们建议通过实验室研究来确定该药物组合对 ROS、Trx 的体内影响 和淋巴瘤患者的线粒体蛋白酶活性。进一步预计，教训 从这些研究中学到的知识将支持我们的长期目标，即了解临床潜力 NHL 中的亲电子化合物家族，其中还包括小白菊内酯、黄瓜素和 阿西维辛，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 治疗 NHL 患者的有效方法。

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.