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 #
5P50CA100707-12
Application #
8764973
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$301,819
Indirect Cost
$117,541
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Guang, Matthew Ho Zhi; McCann, Amanda; Bianchi, Giada et al. (2018) Overcoming multiple myeloma drug resistance in the era of cancer 'omics'. Leuk Lymphoma 59:542-561

Showing the most recent 10 out of 407 publications