Targeting the Mitochondria to Treat Lymphoma and Myeloma

描述（申请人提供）：抗凋亡是非霍奇金淋巴瘤（NHL）和多发性骨髓瘤细胞存活的重要机制。我们已经证明骨髓瘤和NHL的细胞凋亡部分依赖于活性氧（ROS）诱导的促氧化状态的增加。线粒体作为多发性骨髓瘤和NHL中细胞凋亡的主要介质之一发挥重要作用。通过药理学操作使细胞氧化还原平衡倾斜，有利于增加细胞内ROS和/或消耗保护性还原代谢物（如谷胱甘肽），将导致氧化应激和随后诱导肿瘤凋亡。莫替沙芬钆（MGd）是一种新型的金属卟啉剂，已被证明可诱导恶性肿瘤的细胞凋亡和氧化应激。尽管在各种多发性骨髓瘤和NHL临床前模型中记录了通过氧化还原调节靶向线粒体的效果，但很少有临床试验测试了这种创新的治疗概念。本申请的中心假设是MGd将是一种安全有效的药物，其将靶向线粒体，操纵细胞氧化还原系统并以肿瘤选择性方式诱导细胞凋亡，用于治疗复发性/难治性多发性骨髓瘤和NHL患者。我们基于初步数据阐述了这一假设。其中我们已经证明了MGd通过在抗性骨髓瘤和NHL细胞系中的氧化还原和凋亡机制的剂量依赖性细胞毒性。我们将通过以下具体目标来研究这一假设：目标1：确定通过细胞氧化还原调节靶向线粒体治疗复发性或难治性多发性骨髓瘤的临床获益率和安全性。目的2：确定细胞氧化还原调节联合放射免疫治疗复发性或难治性NHL的安全性。目标3：研究多发性骨髓瘤和NHL中MGd治疗后细胞氧化还原系统的体内调节、细胞凋亡诱导和肿瘤选择性生物定位。这些研究将是重要的，因为它们有望为血液恶性肿瘤的治疗提供新的靶点，并将推进对氧化应激和细胞凋亡的基本理解。

DESCRIPTION (provided by applicant): Resistance to apoptosis is an important mechanism of cell survival for non-Hodgkin's lymphoma (NHL) and multiple myeloma. We have documented that apoptosis of myeloma and NHL is in part dependent on an increased pro-oxidant state induced by reactive oxygen species (ROS). Mitochondria plays an important role as one of the primary mediators of apoptosis in multiple myeloma and NHL. Tipping the cellular redox balance through pharmacologic manipulation in favor of increasing intracellular ROS and/or depleting protective reducing metabolites (such as glutathione) will lead to oxidative stress and subsequent induction of tumor apoptosis. Motexafin gadolinium (MGd) is a novel metolloporphyrin agent that has been proven to induce apoptosis and oxidative stress in malignancy. Despite the documented effect of targeting the mitochondria through redox-regulation in various multiple myeloma and NHL pre-clinical models, few clinical trials have tested this innovative therapeutic concept. The central hypothesis of the application is that MGd will be a safe and efficacious a gent that will target the mitochondria, manipulate the cellular redox system and induce apoptosis in a tumor-selective manner for the treatment of patients with relapsed/refractory multiple myeloma and NHL, We have formulated this hypothesis on the basis of preliminary data, in which we have demonstrated dose-dependent cytotoxicity of MGd through redox and apoptotic mechanisms in resistant myeloma and NHL cell lines. We will investigate this hypothesis by the following specific aims: Aim 1: Determine the clinical benefit rate and the safety of targeting the mitochondria through cellular redox regulation for the treatment of relapsed or refractory multiple myeloma. Aim 2: Determine the safety of cellular redox regulation in combination with radioimmunotherapy for the treatment of relapsed or refractory NHL. Aim 3: Investigate in vivo modulation of the cellular redox system, induction of apoptosis and tumorselective biolocalization following MGd therapy in multiple myeloma and NHL. These investigations will be significant, as they are expected to provide a new target for the treatment of hematologic malignancies and will advance the fundamental understanding of oxidative stress and apoptosis.