By Kenneth Anderson, MD

2009-03-01

Dr. Anderson indicated no relevant conflicts of interest.

Kuhn DJ, Hunsucker SA, Chen Q, et al. Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and non-specific proteasome inhibitors. Blood. 2008. [Epub ahead of print]

Kuhn and colleagues report on the novel strategy of targeting the immunoproteasome to overcome bortezomib resistance on the one hand, and avoid side effects on the other. The core proteasome (20S) protease complex is composed of α and β subunits; the β1, β2, and β5 subunits mediate caspase-like (C-L), trypsin-like (T-L), and chymotrypsin-like (CT-L) activities. The corresponding interferon-inducible subunits of the proteasome are the β1i, β2i, and β5i subunits of the immunoproteasome, which enhance the generation of antigenic peptides for MHC Class I presentation. In this study PSI-001, a selective inhibitor of β1i, is shown to overcome resistance to proteasome inhibitor bortezomib in preclinical models. Moreover, the data suggest that neuropathy may not be induced by this more selective β1i inhibitor, providing the framework for clinical trials of selective immunoproteasome inhibitors to improve outcome and lessen toxicity in multiple myeloma (MM).

Proteasome inhibition has achieved remarkable anti-tumor activity and can overcome cell adhesion-mediated drug resistance to conventional therapies in both in vitro and in vivo models of MM cells in the bone marrow microenvironment.^1,2 Moreover, remarkable extent and frequency of response in MM were observed in phase I clinical trials.³ Based upon durable responses with associated clinical benefit in patients with relapsed refractory,⁴ relapsed,⁵ and newly diagnosed⁶ MM, bortezomib was FDA-approved for treatment in these settings in 2003, 2005, and 2008, respectively. However, its use is associated with neuropathy and thrombocytopenia. Moreover, not all patients respond, and those that do eventually develop resistance. Acquired mutations in proteasome subunits have been associated with bortezomib resistance.⁷ Carfilzomib and CEP-18770 both more potently inhibit the CT-L activity, as does bortezomib, whereas NPI0052 inhibits the CT-L activity as well as the T-L and C-L activities.^8,9 All can overcome bortezomib resistance in preclinical studies and are undergoing clinical evaluation. Alternatively, heat shock protein 90 inhibitors,¹⁰ Akt inhibitors,¹¹ and histone deacetylase inhibitors^12-14 have each been combined with bortezomib to overcome bortezomib resistance in preclinical and early-phase clinical trials; these combinations are each now undergoing evaluation in randomized phase III clinical trials for FDA registration. Finally, we have shown in preclinical models that combinations of proteasome inhibitors bortezomib and NPI0052, even at doses which are ineffective alone, can achieve synergistic cytotoxicity with a very favorable side effect profile.¹⁵

Of note, carfilzomib, CEP-18770, and NPI0052 all inhibit both constitutive and immunoproteasome activities; and we have shown that bortezomib inhibits β5 and β1 constitutive as well as immunoproteasome subunit activities to a similar extent in MM cells.¹⁶ Therefore, whether the more selective inhibition of immunoproteasome activity, as reported here, will overcome clinical bortezomib resistance remains to be determined. Importantly, immunoproteasomes are restricted to hematologic cells, suggesting a more favorable therapeutic index than these inhibitors of the constitutive proteasome activities. However, whether inhibition of the immunoproteasome confers immunosuppression needs to be a particular focus of clinical trials. Importantly, fluorogenic substrates are now available to evaluate both the constitutive and immunoproteasome subunit activities¹⁷ in MM cells before and after treatment to correlate the extent of qualitative and quantitative inhibition of the constitutive versus immunoproteasome activity with tumor response versus side effect profile. These studies will provide the rationale for next-generation, more potent and less toxic, single-agent or combination inhibitor approaches, thereby expanding the spectrum of patients benefiting from proteasome inhibitor therapeutic strategies.

1. Hideshima T, Richardson P, Chauhan D, et al. The proteosome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071-6.

2. 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.

3. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002;20:4420-7.

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.

6. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-17.

7. Oerlemans R, Franke NE, Assaraf YG, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112:2489-99.

8. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281-90.

9. Piva R, Ruggeri B, Williams M, et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood. 2008;111:2765-75.

10. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA. 2002;99:14374-9.

11. Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkyl-lysophospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107:4053-62.

12. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101:540-5.

13. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic anti-tumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567-72.

14. Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006;108:3441-9.

15. Chauhan D, Singh A, Brahmandam M, et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood. 2008;111:1654-64.

16. Altun M, Galardy P, Shringapure R, et al. Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Res. 2005;65:7896-901.

17. Ovaa H. Active-site directed probes to report enzymatic action in the ubiquitin proteasome system. Nat Rev Cancer. 2007;7:613-20.

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