Normal cellular homeostasis is maintained by a balanced regulation of protein synthesis and degradation. The ubiquitin proteasome system (UPS) is a non-lysosomal intracellular protein degradation pathway mediated via proteasome holoenzymes, ubiquitin ligases, and deubiquitylating enzymes (DUBs). Deregulation of the UPS pathway is linked to the pathogenesis of various human diseases including multiple myeloma (MM);therefore, inhibitors of UPS pathways, either at the level of proteasomal or ubiquitylating/deubiquitylating enzymes, offers great promise as a novel therapeutic strategy. In our first funding period, we characterized targeting of UPS in MM at the level of the proteasome using our in vitro and in vivo models of the MM cell in the BM milieu. We specifically elucidated the molecular and cellular mechanisms whereby proteasome inhibitors target tumor cells, host tumor interactions, and the BM microenvironment to overcome drug resistance. Our preclinical and clinical studies led to the FDA approval of Bortezomib for relapsed/refractory and newly diagnosed MM. Although Bortezomib represents a major advance, not all patients respond, and those that respond relapse. Therefore our more recent studies have defined mechanisms of resistance to proteasome inhibitors and strategies to overcome it. This work has led to second-generation proteasome inhibitors on the one hand, and scientifically-informed combination therapies on the other, leading to multiple ongoing phase III clinical trials. Our recent efforts have focused on discovery and development of small molecule inhibitors of another major component of UPS, DUBs. Our Preliminary Studies show increased expression and activity of the DUB USP7 in MM cells versus normal plasma cells, and that its inhibition triggers apoptosis even in Bortezomib resistant MM cells. The current proposal aims to investigate the hypothesis that inhibition of the UPS at the level of DUBs, upstream of the proteasome, can inhibit MM cell growth and overcome proteasome inhibitor resistance. To achieve these goals, we will pursue the following Specific Aims:
Specific Aim 1 : To characterize the role of deubiquitylating enzymes (DUBs) in MM cell growth, survival, and drug resistance.
Specific Aim 2 : To develop selective DUB inhibitors and define their in vitro mechanism of action, either alone or in combination with anti-MM agents.
Specific Aim 3 : To conduct preclinical in vivo studies and clinical trials of DUB inhibitors, either alone or in combination, in relapsed refractory MM. This new paradigm to target UPS pathways in MM, either at the level of proteasome or deubiquitylating enzymes, has great promise not only to change the natural history of MM, but also to serve as a model for targeted therapeutics in other cancers.
This new paradigm to target UPS pathways in MM, either at the level of proteasome or deubiquitylating enzymes, has great promise not only to change the natural history of MM, but also to serve as a model for targeted therapeutics in other cancers.
|Ye, Shuai; Lawlor, Matthew A; Rivera-Reyes, Adrian et al. (2018) YAP1-Mediated Suppression of USP31 Enhances NF?B Activity to Promote Sarcomagenesis. Cancer Res 78:2705-2720|
|Hunter, Zachary R; Xu, Lian; Tsakmaklis, Nickolas et al. (2018) Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia. Blood Adv 2:2937-2946|
|Szalat, R; Samur, M K; Fulciniti, M et al. (2018) Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia 32:111-119|
|Bolli, Niccolò; Maura, Francesco; Minvielle, Stephane et al. (2018) Genomic patterns of progression in smoldering multiple myeloma. Nat Commun 9:3363|
|Gullà, A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002|
|Mazzotti, Céline; Buisson, Laure; Maheo, Sabrina et al. (2018) Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv 2:2811-2813|
|Samur, Mehmet Kemal; Minvielle, Stephane; Gulla, Annamaria et al. (2018) Long intergenic non-coding RNAs have an independent impact on survival in multiple myeloma. Leukemia 32:2626-2635|
|Xu, Yan; Deng, Shuhui; Mao, Xuehan et al. (2018) Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma. Clin Lymphoma Myeloma Leuk 18:422-430|
|Michallet, M; Chapuis-Cellier, C; Dejoie, T et al. (2018) Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients. Leukemia 32:376-382|
|Ray, A; Das, D S; Song, Y et al. (2018) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32:843-846|
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