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PMID: 22726549 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

The immunoproteasome as a target in hematologic malignancies.

Seminars in hematology ·Vol. 49 ·No. 3 ·2012-07-00 ·Pages 258-62

Kuhn DJ, Orlowski RZ

Abstract

Suppression of proteasome function with the first-in-class small molecule inhibitor bortezomib is a rational therapeutic strategy against several hematologic malignancies, including multiple myeloma and mantle cell lymphoma. Second-generation inhibitors such as carfilzomib, ixazomib, and marizomib that, like bortezomib, target both the constitutive proteasome and the immunoproteasome, are also in clinical trials and showing encouraging activity. While the efficacy of these agents is well documented, toxicities associated with their use, such as peripheral neuropathy and gastrointestinal effects, can necessitate dose reductions or even discontinuations, possibly hampering their anti-neoplastic effects. These findings suggested that it could be possible to improve the therapeutic index of this class of drugs by specifically targeting only the immunoproteasome. Since the immunoproteasome is a unique target found in lymphoid-derived cells, immunoproteasome-specific inhibitors (IPSIs) could preserve efficacy while reducing treatment-emergent toxicities since they would spare other tissues with little to no immunoproteasome expression. This review discusses the current state of development of IPSIs, and the potential of using such agents for the treatment of hematologic malignancies.

MeSH Terms
Animals Antineoplastic Agents/pharmacology,therapeutic use Hematologic Neoplasms/drug therapy,enzymology,immunology,pathology Humans Proteasome Endopeptidase Complex/immunology,metabolism Proteasome Inhibitors/pharmacology,therapeutic use
Chemicals
Antineoplastic Agents Proteasome Inhibitors Proteasome Endopeptidase Complex
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kuhn Deborah J
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Orlowski Robert Z
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Article Info
Journal
Seminars in hematology
Abbr.
Semin Hematol
ISSN
1532-8686
DOI
10.1053/j.seminhematol.2012.04.003
Published
2012-07-00
Pages
258-62
Language
English
Region
United States
NLM ID
0404514
PMCID
PMC3863635
Subset
IM
Grants
NCI NIH HHS · K99 CA149140 · United States
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · P50 CA142509 · United States
NCI NIH HHS · 1K99 CA149140 · United States
External Links
PubMed source DOI: 10.1053/j.seminhematol.2012.04.003 PMC Full Text View journal details
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