Proteasome Inhibitors in Treatment of Multiple Myeloma


Authors: L. Kubiczková;  J. Matějíková;  L. Sedlaříková;  F. Kryukov;  R. Hájek;  S. Ševčíková
Authors‘ workplace: Babákova myelomová skupina, Ústav patologické fyziologie, LF MU Brno
Published in: Klin Onkol 2013; 26(1): 11-18
Category: Reviews

Overview

Multiple myeloma, a plasma cell malignancy, still remains a hard-to-treat hematological disease that desperately needs new therapy targeting plasmocytes but also the bone marrow microenvironment. Clonal plasmocytes are characterized by increased regulation of ubiquitin-proteasome pathway which augments their sensitivity to proteasome inhibitors. Treatment strategies based on proteasome inhibitors belong to the era of new drugs, and they have become increasingly important for treatment of multiple myeloma in recent years. Bortezomib became the first proteasome inhibitor approved for the treatment of multiple myeloma and showed remarkable anti-myeloma activity. However, despite its high efficiency, a large proportion of patients have became bortezomib resistant. The second generation of proteasome inhibitors – carfilzomib, marizomib and MLN9708 – were developed in an effort to overcome bortezomib-resistance and find proteasome inhibitors with a better toxic profile. These drugs brought a chance that multiple myeloma would become a chronic disease.

Key words:
multiple myeloma – proteasome inhibitors – bortezomib – carfilzomib – marizomib – MLN9708


Sources

1. Harris JR. The proteins released from intact erythrocyte ghosts‘ at low ionic strength. Biochem J 1971; 122(5): 38P–40P.

2. Ciehanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun 1978; 81(4): 1100–1105.

3. Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J 1998; 17(24): 7151–7160.

4. Unno M, Mizushima T, Morimoto Y et al. The structure of the mammalian 20S proteasome at 2.75 A resolution. Structure 2002; 10(5): 609–618.

5. Jäger S, Groll M, Huber R et al. Proteasome beta-type subunits: unequal roles of propeptides in core particle maturation and a hierarchy of active site function. J Mol Biol 1999; 291(4): 997–1013.

6. Arendt CS, Hochstrasser M. Identification of the yeast 20S proteasome catalytic centers and subunit interac­tions required foractive-siteformation. Proc Natl Acad Sci U S A 1997; 94(14): 7156–7161.

7. Parlati F, Lee S, Aujay M et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 2009; 114(16): 3439–3447.

8. Carvalho P, Goder V, Rapoport TA. Distinct Ubiquitin-Ligase Complexes Define Convergent Pathways for the Degradation of ER Proteins. Cell 2006; 126(2): 361–373.

9. Luciani F, Keşmir C, Mishto M et al. A mathematical model of protein degradation by the proteasome. Biophys J 2005; 88(4): 2422–2432.

10. Adam Z, Ščudla V, Neubauer J. Mnohočetný myelom. In: Adam Z, Vorlíček J, Adamová Z et al. Hematologie II: Přehled maligních hematologických nemocí. Praha: Grada 2001: 461–498.

11. Goldberg AL. Introduction to the proteasome and its inhibitors. In: Adams J. Proteasome inhibtors in cancer therapy. New Jersey: Humana Press 2004: 17–39.

12. Adams J, Palombella VJ, Sausville EA et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59(11): 2615–2622.

13. 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(22): 4420–4427.

14. Kane RC, Bross PF, Farrell AT et al. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003; 8(6): 508–513.

15. Špička I, Kleibl Z, Hájek R. Bortezomibum. Remedia 2005; 15(3): 193–203.

16. Berkers CR, Verdoes M, Lichtman E et al. Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nat Methods 2005; 2(5): 357–362.

17. Groll M, Berkers CR, Ploegh HL et al. Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 2006; 14(3): 451–456.

18. Richardson PG, Sonneveld P, Schuster MW et al. Assessment of Proteasome Inhibition for Extending Remis­sions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352(24): 2487–2498.

19. Hideshima T, Chauhan D, Richardson P et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277(19): 16639–16647.

20. Hideshima T, Ikeda H, Chauhan D et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 2009; 114(5): 1046–1052.

21. Mitsiades N, Mitsiades CS, Poulaki V et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002; 99(22): 14374–14379.

22. Hideshima T, Mitsiades C, Akiyama M et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101(4):1530–1534.

23. Hideshima T, Richardson P, Chauhan D et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61(7): 3071–3076.

24. Mukherjee S, Raje N, Schoonmaker JA et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest 2008; 118(2): 491–504.

25. Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348(26): 2609–2617.

26. Jagannath S, Barlogie B, Berenson J et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004; 127(2): 165–172.

27. Mateos MV, Richardson PG, Schlag R et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J ClinOncol 2010; 28(13): 2259–2266.

28. Moreau P, Pylypenko H, Grosicki S et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12(5): 431–440.

29. Hájek R, Adam Z, Maisnar V et al. Diagnostika a léčba mnohočetného myelomu. Transfuze Hematol dnes 2012; 18 (Suppl 1): 1–80.

30. Arastu-Kapur S, Anderl JL, Kraus M et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 2011; 17(9): 2734–2743.

31. 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(6): 2489–2499.

32. Smith AJ, Dai H, Correia C et al. Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. J Biol Chem 2011; 286(20): 17682–17692.

33. Chauhan D, Catley L, Li G et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005; 8(5): 407–419.

34. Zhang L, Littlejohn JE, Cui Y et al. Characterization of bortezomib-adapted I-45 mesothelioma cells. Mol Cancer 2010; 9: 110.

35. Zou W, Yue P, Lin N et al. Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells. Clin Cancer Res 2006; 12(1): 273–280.

36. Golden EB, Lam PY, Kardosh A et al. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood 2009; 113(23): 5927–5937.

37. Lonial S, Boise LH. Current Advances in Novel Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma. Oncology 2011; 25(2).

38. 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(9): 3281–3290.

39. Demo SD, Kirk CJ, Aujay MA et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007; 67(13): 6383–6391.

40. Suzuki E, Demo S, Arastu-Kapur S et al. Bortezomib resistant cell lines have increased proteasome levels but remain sensitive to carfilzomib. Blood 2009; 114: Abstr 2852.

41. Wang L, Kumar S, Fridley B et al. Proteasome beta subunit pharmacogenomics: gene resequencing and func­tional genomics. Clin Cancer Res 2008; 14(11): 3503–3513.

42. Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol 2001; 8(8): 739–758.

43. Ruschak AM, Slassi M, Kay LE et al. Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst 2011; 103(13): 1007–1017.

44. O‘Connor OA, Stewart AK, Vallone M et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 2009; 15(22): 7085–7091.

45. Niesvizky R, Bensinger W, Vallone M et al. PX-171–006: Phase Ib multicenter dose escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) and low-dose dexamethasone (loDex) in relapsed and refractory multiple myeloma (MM): Preliminary results (Abstract). J Clin Oncol 2009; 27 (15 Suppl); Abstr 8541.

46. Vij R, Wang M, Kaufman JL et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012; 119(24): 5661–5670.

47. Jakubowiak AJ, Dytfeld D, Griffith KA et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012; 120(9): 1801–1089.

48. Fenical W, Jensen PR. Developing a new resource for drug discovery: marine actinomycete bacteria. Nat Chem Biol 2006; 2(12): 666–673.

49. Miller CP, Manton CA, Hale R et al. Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs. Chem Biol Int 2011; 194(1): 58–68.

50. Hofmeister CC, Richardson P, Zimmerman T et al. Clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (r/r MM). J Clin Oncol 2009; 27 (15 Suppl): Abstr 8505.

51. Ocio EM, Mateos MV, San-Miguel JF. Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs. Expert Opin Investig Drugs 2012; 21(8): 1075–1087.

52. Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies. Semin Hematol 2012; 49 (Suppl 1): S33–S46.

53. Chauhan D, Tian Z, Zhou B et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011; 17(16): 5311–5321.

54. Lee EC, Fitzgerald M, Bannerman B et al. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res 2011; 17(23): 7313–7323.

55. Kupperman E, Lee EC, Cao Y et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010; 70(5): 1970–1980.

56. Tian Z, Zhao JJ, Tai YT et al. Investigational agent MLN9708/2238 targets tumor suppressor microRNA-33b in MM cells. Blood 2012; 120(19): 3958–3967.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account