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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA100707-11A1
Application #
8607269
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Project Start
2003-09-01
Project End
2018-08-31
Budget Start
2013-09-18
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$298,004
Indirect Cost
$116,055
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Das, D Sharma; Ray, A; Das, A et al. (2016) A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia 30:2187-2197
Tagde, Ashujit; Rajabi, Hasan; Stroopinsky, Dina et al. (2016) MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia. Oncotarget 7:38974-38987
Lin, Jianhong; Zhang, Weihong; Zhao, Jian-Jun et al. (2016) A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy. Blood 128:249-52
Hunter, Zachary R; Xu, Lian; Yang, Guang et al. (2016) Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. Blood 128:827-38
Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S et al. (2016) A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409
Mullikin, Trey C; Rajkumar, S Vincent; Dispenzieri, Angela et al. (2016) Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol 91:473-5
An, Gang; Acharya, Chirag; Feng, Xiaoyan et al. (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590-603
Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey et al. (2016) MUC1-C drives MYC in multiple myeloma. Blood 127:2587-97
Jiang, H; Acharya, C; An, G et al. (2016) SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 30:399-408
Gullà, Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33

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