Project 2:The triterpenoids are novel electrophilic compounds that we have shown induce apoptotic cell death inmantle cell lymphoma (MCL) and diffuse large cell lymphoma (DLCL). Indeed our published and preliminarystudies suggest that these compounds manifest their cytotoxic effects by both increasing the generation ofreactive oxygen species (ROS), and decreasing the activity of such critical anti-oxidant defense mechanismsas thioredoxin (Trx) and the mitochondria! proteases, Lon and CIpXP. This suggests a novel therapeuticstrategy for lymphoma based on modulating the lymphoma cell redox state. In addition, our proposedmechanism suggests that other redox active agents, such as proteosome inhibitors and histone deacetylaseinhibitors, are rationale agents to combine with the triterpenoids.
The Specific Aims of this proposal havebeen developed to provide the essential pre-clinical data needed to support the clinical evaluation of theoptimal 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 tooptimize triterpenoid drug combinations in vitro. These combinations will be further optimized and thebiological targets of ROS generation, Trx and mitochondrial proteases validated in vivo using DLCL andMCL/SCID xenograft models in Specific Aim 2. We anticipate that the data derived from these Specific Aimswill suggest an optimal triterpenoid combination, and sequence of drug delivery to be studied in the contextof a phase l/ll trial as proposed in Specific Aim 3. A critical component of this trial will be the correlativelaboratory studies whereby we propose to determine the in vivo effects of this drug combination on ROS, Trxand mitochondrial protease activity in patients with lymphoma. It is further anticipated that the lessonslearned from these studies will support our long term goals which are to understand the clinical potential ofthe family of electrophilic compounds in NHL, which also includes the parthenolides, cucurmin, and theacivicins, and more importantly how best to exploit the redox state of lymphoma to generate new andeffective approaches for the treatment of patients with NHL.
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