Targeting the Mitochondria to Treat Lymphoma and Myeloma

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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.