Demo SD, Kirk CJ, Aujay MA, et al. . Cancer Res. 2007;67:6383-91.
Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome
 

A new treatment paradigm targeting the tumor cell and its BM microenvironment to overcome drug resistance and improve patient outcome has now been developed in multiple myeloma (MM).1  The boronic acid proteasome inhibitor bortezomib targets the tumor cell in its microenvironment in both laboratory2  and animal models,3  and has rapidly been translated from the bench to the bedside and ultimately FDA approval first for treatment of relapsed refractory MM,4  and subsequently of relapsed MM.5  Bortezomib was then combined with dexamethasone6  or with melphalan and prednisone7  as initial therapy for newly diagnosed patients who were stem cell transplant candidates or elderly non-transplant candidates, respectively, and achieved high extent and frequency of response. However, although bortezomib is a major advance, not all patients respond, and those that do eventually acquire resistance.

Two strategies are under development to sensitize or overcome resistance to bortezomib. First, preclinical studies suggest that bortezomib combined with DNA damaging agents,8  heat shock protein 90 inhibitors,9  Akt inhibitors,10  and histone deacetylase inhibitors11 ,12  mediates synergistic MM cell cytotoxicity; already the combination of bortezomib and pegylated doxorubicin has been FDA-approved for treatment of relapsed MM, as it has achieved significantly increased response rate, extent, and progression-free and overall survival compared to bortezomib alone.13  The second strategy is the development of next-generation proteasome inhibitors, NPI-0052 and PR-171. NPI-0052 inhibits caspase-like, trypsin-like, and chymotrypsin-like proteasome activities; overcomes bortezomib resistance and is well tolerated in preclinical models;14  and is now in a clinical trial in MM.

In the current report, Demo and colleagues report on PR-171, a novel epoxyketone-based irreversible proteasome inhibitor which exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome.15  In preclinical studies at two-day or five-day consecutive schedules, it can inhibit proteasome activity by 80 percent and overcome bortezomib resistance. Additional in vitro data show that it inhibits chymotrypsin-like activity, not only of the proteasome, but also of the immunoproteasome, and induces apoptosis via both intrinsic and extrinsic apoptotic signaling.16  This promising preclinical data has rapidly translated to clinical trials of PR-171, which have achieved responses in relapsed refractory MM when given daily on either two-day or five-day schedules, and two phase II trials are soon to begin in relapsed and in relapsed refractory MM.

These exciting data both confirm the activity of proteasome inhibitors in MM and suggest that more potent chymotrypsin-like inhibition may increase MM cell cytotoxicity. In future clinical trials, gene and protein profiling of patients responsive versus resistant to proteasome inhibitors,17  coupled with the ability to utilize fluorescent probes to assess patterns of qualitative and quantitative proteasome and immunoproteasome inhibition in MM cells associated with response,18  will allow for the optimal use of this exciting class of novel therapeutics.

1.
Hideshima T, Mitsiades C, Tonon G, et al. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585-98.
3.
LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002;62:4996-5000.
4.
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-17.
5.
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-98.
9.
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood. 2006;107:1092-100.
11.
Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567-72.
15.
Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383-91.
18.
Berkers CR, Verdoes M, Lichtman E, et al. Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nature Methods. 2005;2:357-362.

Competing Interests

Dr. Anderson has done research work on proteasome inhibitors for multiple, different pharmaceutical companies.