Aiming at WM with both barrels blocked.

How can a therapy be targeted to cancer if the target is in every normal cell? Because proteasomes are found in all nucleated as well as anucleated cells, it could be argued that this target is even less cancer-specific than that of conventional DNA-damaging chemotherapy. However, proteasome inhibitors clearly have made an impact in the treatment of many types of cancer and none bigger than in B-cell malignancies. Recent studies of proteasome inhibition including those presented here suggest that the answer may be that the target is unique in B-cell malignancies including Waldenström macroglobulinemia (WM). These cells have 2 types of proteasomes that must be inhibited to induce apoptosis, and now this can be achieved with an orally available agent. WM is an IgM-secreting lymphoplasmacytic lymphoma with bone marrow involvement that accounts for 1% to 2% of hematologic malignancies.2 Because WM shares many of the biological characteristics of both lymphomas and multiple myeloma, WM patients have benefited from therapeutic advances in both diseases. Current therapeutic approaches in WM include the use of rituximabcontaining regimens as well as bortezomib, which had single-agent activity and recently was shown to be highly active in combination with rituximab and dexamethasone.2,3 However, bortezomib had to be discontinued in 61% of the patients on this study because of peripheral neuropathy.3 Peripheral neuropathy associated with bortezomib use has led to the development of several second-generation proteasome inhibitors, including the irreversible inhibitor, carfilzomib, that did not induce dose-limiting neuropathy in a phase 1 study of 29 patients with hematologic malignancies.4 Now, an analog of carfilzomib has been developed that is orally bioavailable5 and appears to hold promise for the treatment of WM. In the current study, ONX0912 (formerly PR-047) induced growth inhibition and apoptosis in a dose-dependent fashion in both WM and low-grade IgM-secreting lymphoma cell lines as well in cells from 4 WM patients while having no effect on B cells from healthy donors.1 Using a unique ELISA-based activity assay to capture proteasome-active sites,6 the investigators demonstrated that both the constitutive proteasome and the immunoproteasome are expressed in WM cells at significantly higher levels than normal B cells. While the catabolic requirements of normal resting B cells and IgM-secreting cells are likely to be different, the data do support the notion that B-cell malignancies express both the constitutive proteasome (c20s) and immunoproteasome (i20s) that differ by the catalytic subunits found in the rings of the barrel (red for c20s, blue for i20s). As described in the text, these proteasomes regulate several functions in the cell, some that are specific to the immunoproteasome (found in the blue region) including Ag processing and cytokine production. Other functions of the proteasome may be specific to the c20s (red area) or are regulated by both (overlapping purple area). It remains to be determined whether functions of the proteasome such as NFB activation are regulated by one or both proteasomes. Having essential functions regulated by 2 proteasomes may explain why B-cell malignancies are so sensitive to this class of therapeutic agents. Professional illustration by A. Y. Chen.