The immunoproteasome as a target in hematologic malignancies.
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.
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Deborah J
DJ
Kuhn
Robert Z
RZ
Orlowski
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex