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Myeloma

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

Leukemia volume 23, pages 961–970 (2009)Cite this article

Abstract

Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

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References

  1. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC . Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–618.

    Article  CAS  PubMed  Google Scholar 

  2. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC . Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007; 7: 585–598.

    Article  CAS  PubMed  Google Scholar 

  3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.

    Article  PubMed  Google Scholar 

  4. Raje N, Anderson K . Thalidomide—a revival story. N Engl J Med 1999; 341: 1606–1609.

    Article  CAS  PubMed  Google Scholar 

  5. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–1571.

    Article  CAS  PubMed  Google Scholar 

  6. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617.

    Article  CAS  PubMed  Google Scholar 

  7. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.

    Article  CAS  PubMed  Google Scholar 

  8. Raje N, Hideshima T, Anderson KC . Therapeutic use of immunomodulatory drugs in the treatment of multiple myeloma. Expert Rev Anticancer Ther 2006; 6: 1239–1247.

    Article  CAS  PubMed  Google Scholar 

  9. Harousseau JL, Moreau P . Evolving role of stem cell transplantation in multiple myeloma. Clin Lymphoma Myeloma 2005; 6: 89–95.

    Article  PubMed  Google Scholar 

  10. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516–2520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy Jr J . Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005; 106: 296–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bergsagel PL, Kuehl WM . Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005; 23: 6333–6338.

    Article  CAS  PubMed  Google Scholar 

  13. Shaughnessy Jr JD, Barlogie B . Using genomics to identify high-risk myeloma after autologous stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 77–80.

    Article  CAS  PubMed  Google Scholar 

  14. Kuehl WM, Bergsagel PL . Early genetic events provide the basis for a clinical classification of multiple myeloma. Am Soc Hematol Educ Program 2005, 346–352.

    Article  Google Scholar 

  15. Agnelli L, Bicciato S, Mattioli M, Fabris S, Intini D, Verdelli D et al. Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. J Clin Oncol 2005; 23: 7296–7306.

    Article  CAS  PubMed  Google Scholar 

  16. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002; 100: 1417–1424.

    CAS  PubMed  Google Scholar 

  17. Fonseca R, Blood EA, Oken MM, Kyle RA, Dewald GW, Bailey RJ et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood 2002; 99: 3735–3741.

    Article  CAS  PubMed  Google Scholar 

  18. Joshi KS, Rathos MJ, Mahajan P, Wagh V, Shenoy S, Bhatia D et al. P276-00, a novel cyclin-dependent inhibitor induces G1–G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther 2007; 6: 926–934.

    Article  CAS  PubMed  Google Scholar 

  19. Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S et al. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol Cancer Ther 2007; 6: 918–925.

    Article  CAS  PubMed  Google Scholar 

  20. Tai YT, Teoh G, Shima Y, Chauhan D, Treon SP, Raje N et al. Isolation and characterization of human multiple myeloma cell enriched populations. J Immunol Methods 2000; 235: 11–19.

    Article  CAS  PubMed  Google Scholar 

  21. Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006; 9: 313–325.

    Article  CAS  PubMed  Google Scholar 

  22. Nelsen CJ, Kuriyama R, Hirsch B, Negron VC, Lingle WL, Goggin MM et al. Short term cyclin D1 overexpression induces centrosome amplification, mitotic spindle abnormalities, and aneuploidy. J Biol Chem 2005; 280: 768–776.

    Article  CAS  PubMed  Google Scholar 

  23. Raje N, Kumar S, Hideshima T, Ishitsuka K, Chauhan D, Mitsiades C et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 2004; 104: 4188–4193.

    Article  CAS  PubMed  Google Scholar 

  24. Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 2005; 106: 1042–1047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ishii Y, Pirkmaier A, Alvarez JV, Frank DA, Keselman I, Logothetis D et al. Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model. J Natl Cancer Inst 2006; 98: 1238–1247.

    Article  CAS  PubMed  Google Scholar 

  26. Chou TC, Talalay P . Quantitative analysis of dose–effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27–55.

    Article  CAS  PubMed  Google Scholar 

  27. Toogood PL . Cyclin-dependent kinase inhibitors for treating cancer. Med Res Rev 2001; 21: 487–498.

    Article  CAS  PubMed  Google Scholar 

  28. Chen-Kiang S . Cell-cycle control of plasma cell differentiation and tumorigenesis. Immunol Rev 2003; 194: 39–47.

    Article  CAS  PubMed  Google Scholar 

  29. Ely S, Di Liberto M, Niesvizky R, Baughn LB, Cho HJ, Hatada EN et al. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Res 2005; 65: 11345–11353.

    Article  CAS  PubMed  Google Scholar 

  30. Swanton C . Cell-cycle targeted therapies. Lancet Oncol 2004; 5: 27–36.

    Article  CAS  PubMed  Google Scholar 

  31. Malumbres M, Pevarello P, Barbacid M, Bischoff JR . CDK inhibitors in cancer therapy: what is next? Trends Pharmacol Sci 2008; 1: 16–21.

    Article  Google Scholar 

  32. Krieger S, Gauduchon J, Roussel M, Troussard X, Sola B . Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma. BMC Cancer 2006; 6: 238.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kozar K, Sicinski P . Cell cycle progression without cyclin D-CDK4 and cyclin D-CDK6 complexes. Cell Cycle 2005; 4: 388–391.

    Article  CAS  PubMed  Google Scholar 

  34. Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 2004; 118: 477–491.

    Article  CAS  PubMed  Google Scholar 

  35. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 2004; 118: 493–504.

    Article  CAS  PubMed  Google Scholar 

  36. Blagosklonny MV . Flavopiridol, an inhibitor of transcription: implications, problems and solutions. Cell Cycle 2004; 3: 1537–1542.

    Article  CAS  PubMed  Google Scholar 

  37. Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006; 66: 7661–7667.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Multiple Myeloma Research Foundation Awards (NR, NCM and KCA); ASCO Career Development Award (NR); Department of Veterans Affairs merit review grant and the Leukemia and Lymphoma Society Scholar in Translational Research Award (NCM); NIH grants P50-100707 and PO1-78378 (KCA, NCM) as well as NIH grant RO1-50947 (KCA).

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Authors and Affiliations

  1. Division of Hematologic Malignancies, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    N Raje, T Hideshima, M Raab, S Vallet, S Chhetri, D Cirstea, S Pozzi, C Mitsiades, M Rooney, T Kiziltepe, K Podar, Y Okawa, H Ikeda, R Carrasco, P G Richardson, D Chauhan, N C Munshi & K C Anderson

  2. Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    N Raje, S Mukherjee, S Vallet, B Chabner & D Scadden

  3. Nicholas Piramal India Ltd, Mumbai, India

    S Sharma & H Parikh

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Correspondence to N Raje.

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Raje, N., Hideshima, T., Mukherjee, S. et al. Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia 23, 961–970 (2009). https://doi.org/10.1038/leu.2008.378

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