During the previous funding period, we utilized our in vitro and in vivo models of the multiple myeloma (MM)cell in the bone marrow (BM) milieu to demonstrate the molecular mechanisms whereby proteasomeinhibitors target tumor cells, host tumor interactions, and the BM microenvironment to overcomeconventional drug resistance. We then rapidly translated these laboratory findings to the clinic leading to theFDA approval of Bortezomib for relapsed refractory MM in 2003 and relapsed MM in 2005. Importantly, ourcorrelative science studies of patient samples have identified genomic profiles of patients most likely torespond. Although Bortezomib represents a major advance, not all patients respond, those that respondrelapse, and no patients are cured. This proposal will therefore focus on using oncogenomics to definemechanisms of Bortezomib resistance. We will then validate novel targeted therapies to overcomeBortezomib resistance for evaluation in derived clinical trials.. To achieve these goals, we will pursue thefollowing Specific Aims: to define the molecular determinants of proteasome inhibitor resistance usinghigh throughput RNAi screens interrogating the effects of silencing the 'druggable genome' in aproteasome inhibitor resistant MM cell line (Specific Aim 1); to define strategies to overcomeproteasome inhibitor resistance using in vitro preclinical models (Specific Aim 2); and to conductpreclinical in vivo studies and clinical trials to enhance sensitivity or overcome resistance toproteasome inhibitors (Specific Aim 3). This new paradigm to overcome proteasome inhibitor resistancein MM has great promise not only to change the natural history of MM, but also to serve as a model fortargeted therapeutics directed to improve outcome of patients with other hematologic malignancies as wellas solid tumors.
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