Proteasome Inhibitors: Closing the Garbage Can Opens up New Therapeutic Options for Patients with B-Cell Malignancies

Abstract

Recently, the so-called garbage can of the cell, the proteasomeubiquitin system, has become the target for new therapeutics to treat a variety of hematologic malignancies. This system consists of the proteasome, which is a multienzyme complex that plays a key role in degrading many intracellular proteins. Every week, new key proteins are identified that are degraded by this system; these key proteins control cell growth, cell death, and other important cellular functions. The 26S proteasome consists of a 20S core structure shaped in a cylinder that, using multiple catalytic processes, can degrade proteins in an adenosine triphosphate–independent manner. The proteasome also contains a 19S regulatory part that identifies and degrades proteins in an adenosine triphosphate–dependent fashion. Protein and peptides are selected for degradation if they have been ubiquitylated. This latter process is mediated by the coordinated effects of a set of enzymes that tag the proteins selected for degradation with covalently bound ubiquitin moieties that consist of amino acid chains. These tagged proteins bind to the 19S regulatory unit and are deubiquitinated and unfolded. Subsequently, the proteins are degraded into small peptides as they move through the 20S cylindrical structure. The recent demonstration of the efficacy of the boroncontaining dipeptide proteasome inhibitor bortezomib in treating a variety of B-cell malignancies has opened the door for the development of many similar drugs to block the proteasome, including the irreversible inhibitor PR-171, a derivative of epoxomycin, and NPI-0052, a lactacystin-related non-peptide.1,2 These 2 drugs have shown promise in preclinical studies and are currently in clinical development for the treatment of multiple myeloma (MM) and other malignancies. Because of the great number of proteins that are degraded through the proteasomeubiquitin system, the target(s) for the antitumor activity of these drugs remains unclear. Certainly, inhibition of the activity of the transcription factor nuclear factor–κB is thought to play a role in the activity of bortezomib, although other candidates have also recently been identified.3 Notably, these drugs have also shown the ability to overcome chemotherapy resistance.4,5 This has led to their use in combination with other agents active in B-cell tumors, with excellent clinical results observed.6,7 The recent Food and Drug Administration approval of the combination of bortezomib with pegylated liposomal doxorubicin for the treatment of relapsed/refractory MM attests to the efficacy of this approach. Importantly, when used in combination with chemotherapy, bortezomib and a number of different chemotherapeutic agents have been shown to be highly effective at lower doses. Because the major side effects of bortezomib are different from the adverse effects of chemotherapy, these new regimens utilizing lower drug doses are not only showing high response rates, but are also likely to be better tolerated; early clinical experience supports this beneficial effect. Exciting recent preclinical results suggest that the proteasome inhibitor’s antitumor effects might be enhanced by a variety of new classes of drugs, including p38 mitogen-activated protein kinase, farnesyl transferase, and histone deacetylase inhibitors.8-10 Because bortezomib is also radiosensitizing, clinical trials are being conducted in patients with MM using this agent combined with bone-seeking radionuclides such as samarium153 lexidronam with promising early clinical results.11 In this issue of Clinical Lymphoma & Myeloma, a series of articles review new treatments for a variety of B-cell malignancies, including non-Hodgkin lymphoma, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, and MM. In addition to bortezomib, thalidomide or lenalidomide in combination with glucocorticosteroids have recently been Food and Drug Administration approved for the treatment of MM. Specifically, Jagannath outlines the many new first-line therapeutic options for patients with MM, including the combination of thalidomide or lenalidomide with glucocorticosteroids and/or melphalan. Similarly, bortezomib has also been combined with glucocorticosteroids or chemotherapy, with high response rates. Lee and Munshi summarize the many new therapeutic targets in preclinical and clinical development for MM. Many new drugs are in early development, including inhibitors of histone deacetylase, farnesyl transferase, p38 mitogen-activated protein kinase, heat-shock protein 90, the mammalian target of rapamycin pathway, and vascular endothelial growth factor. These drugs have different mechanisms of antimyeloma activity that not only directly inhibit myeloma cells, but in some cases, also affect the bone marrow microenvironment as well as work through immune-mediated mechanisms of action. Treon and colleagues have updated the many options now available for patients with Waldenstrom’s macroglobulinemia. In addition to the demonstrated efficacy of bortezomib