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Novel therapies in MM: from the aspect of preclinical studies

  • Progress in Hematology
  • Understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

During the last decade, thalidomide, lenalidomide, and bortezomib have been approved by the US Food and Drug Administration for the treatment of MM; however, MM remains incurable. The development and progression of multiple myeloma (MM) is a complex multi-step process involving genetic abnormalities in tumor cells at both early and late stages. Moreover, soluble factors and cell–cell contact within the tumor bone marrow (BM) microenvironment promotes MM cell growth, survival, and drug resistance. A number of novel agents targeting both tumor cells and growth factors in the BM milieu have been developed. Currently they are under evaluation in preclinical studies, as single agents and/or in combination, to improve outcome of MM patients.

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References

  1. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer. 2002;2:927–37.

    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;7:585–98.

    Article  CAS  PubMed  Google Scholar 

  3. Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B, Stewart JP, Zhan F, Khatry D, Protopopova M, Protopopov A, Sukhdeo K, Hanamura I, Stephens O, Barlogie B, Anderson KC, Chin L, Shaughnessy JD Jr, Brennan C, Depinho RA. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;9:313–25.

    Article  CAS  PubMed  Google Scholar 

  4. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ, Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Stewart AK, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, Getz G, Golub TR. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hideshima T, Podar K, Chauhan D, Anderson KC. Cytokines and signal transduction. Best Pract Res Clin Haematol. 2005;18:509–24.

    Article  CAS  PubMed  Google Scholar 

  6. Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, Corringham RE, Zaki MH, Nemeth JA, Orlowski RZ. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res. 2007;13:6469–78.

    Article  CAS  PubMed  Google Scholar 

  7. Rossi J-F, Manges RF, Sutherland HJ, Jagannath S, Voorhees P, Sonneveld P, Delforge M, Pegourie B, Alegre A, de la Rubia J, La Police D, Bandekar R, Xie H, Orlowski RZ. Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood. 2008;112:320.

    Article  Google Scholar 

  8. Hunsucker SA, Magarotto V, Kuhn DJ, Kornblau SM, Wang M, Weber DM, Thomas SK, Shah JJ, Voorhees PM, Xie H, Cornfeld M, Nemeth JA, Orlowski RZ. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. Br J Haematol. 2011;152:579–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, Shen Z, Patel N, Tai YT, Chauhan D, Mitsiades C, Prabhala R, Raje N, Anderson KC, Stover DR, Munshi NC. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009;114:371–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC, Kung AL. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5:221–30.

    Article  CAS  PubMed  Google Scholar 

  11. Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J, Chen C, Discenza L, Menard K, Li A, Trainor G, Vyas D, Kramer R, Attar RM, Gottardis MM. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009;8:3341–9.

    Article  CAS  PubMed  Google Scholar 

  12. Liang Y, Mao X, Liu H. Proteasome inhibitor clioquinol as a candidate drug in prophylaxis and treatment of acute graft-versus-host disease. Med Hypotheses. 2011;76:400–2.

    Article  CAS  PubMed  Google Scholar 

  13. Bisping G, Leo R, Wenning D, Dankbar B, Padro T, Kropff M, Scheffold C, Kroger M, Mesters RM, Berdel WE, Kienast J. Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood. 2003;101:2775–83.

    Article  CAS  PubMed  Google Scholar 

  14. Chang H, Stewart AK, Qi XY, Li ZH, Yi QL, Trudel S. Immunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma. Blood. 2005;106:353–5.

    Article  CAS  PubMed  Google Scholar 

  15. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005;105:2941–8.

    Article  CAS  PubMed  Google Scholar 

  16. Trudel S, Stewart AK, Rom E, Wei E, Li ZH, Kotzer S, Chumakov I, Singer Y, Chang H, Liang SB, Yayon A. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood. 2006;107:4039–46.

    Article  CAS  PubMed  Google Scholar 

  17. Krejci P, Murakami S, Prochazkova J, Trantirek L, Chlebova K, Ouyang Z, Aklian A, Smutny J, Bryja V, Kozubik A, Wilcox WR. NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells. J Biol Chem. 2010;285:20644–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Scuto A, Krejci P, Popplewell L, Wu J, Wang Y, Kujawski M, Kowolik C, Xin H, Chen L, Kretzner L, Yu H, Wilcox WR, Yen Y, Forman S, Jove R. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia. 2011;25:538–50.

    Article  CAS  PubMed  Google Scholar 

  19. Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH, Lokhorst HM, Bloem AC, Clevers H, Nusse R, van der Neut R, Spaargaren M, Pals ST. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci USA. 2004;101:6122–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, Carrasco DE, Zheng M, He H, Tai YT, Mitsiades C, Anderson KC, Carrasco DR. Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci USA. 2007;104:7516–21.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J, Barlogie B, Shaughnessy JD Jr. Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood. 2008;112:196–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama T. DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene. 2004;23:8520–26.

    Article  CAS  PubMed  Google Scholar 

  23. Qian J, Xie J, Hong S, Yang J, Zhang L, Han X, Wang M, Zhan F, Shaughnessy JD Jr, Epstein J, Kwak LW, Yi Q. Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma. Blood. 2007;110:1587–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–94.

    Article  CAS  PubMed  Google Scholar 

  25. Colla S, Zhan F, Xiong W, Wu X, Xu H, Stephens O, Yaccoby S, Epstein J, Barlogie B, Shaughnessy JD Jr. The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells. Blood. 2007;109:4470–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pozzi S, Yan H, Vallet S, Vaghela N, Fulciniti M, Cirstea D, Santo L, Mukherjee S, Hideshima T, Schirtzinger L, Kuhstoss S, Munshi NC, Anderson KC, Scadden D, Raje N. Promoting osteoblastogenesis using a novel Dkk-1 neutralizing antibody in the treatment of multiple myeloma related bone disease. Blood. 2008;112:946.

    Article  Google Scholar 

  27. Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, Lee AI, Podar K, Hideshima T, Rice AG, van Abbema A, Jesaitis L, Caras I, Law D, Weller E, Xie W, Richardson P, Munshi NC, Mathiot C, Avet-Loiseau H, Afar DE, Anderson KC. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112:1329–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R, Balasa B, Ganguly B, Chao D, Rice AG, Zhan F, Shaughnessy JD Jr, Barlogie B, Yaccoby S, Afar DE. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther. 2009;8:2616–24.

    Article  PubMed  PubMed Central  Google Scholar 

  29. de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840–8.

    Article  PubMed  Google Scholar 

  30. van der Veer MS, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PW, Lokhorst HM, Mutis T. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica. 2011;96:284–90.

    Article  PubMed  Google Scholar 

  31. Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, Okawa Y, Kiziltepe T, Santo L, Vallet S, Cristea D, Calabrese E, Gorgun G, Raje NS, Richardson P, Munshi NC, Lannutti BJ, Puri KD, Giese NA, Anderson KC. PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood. 2010;116:1460–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, Santo L, Cirstea D, Patel K, Sohani AR, Guimaraes A, Xie W, Chauhan D, Schoonmaker JA, Attar E, Churchill M, Weller E, Munshi N, Seehra JS, Weissleder R, Anderson KC, Scadden DT, Raje N. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA. 2010;107:5124–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial I, Anderson KC. Targeting MEK induces myeloma cell cytotoxicity and inhibits osteoclastogenesis. Blood. 2007;110:1656–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim K, Kong SY, Fulciniti M, Li X, Song W, Nahar S, Burger P, Rumizen MJ, Podar K, Chauhan D, Hideshima T, Munshi NC, Richardson P, Clark A, Ogden J, Goutopoulos A, Rastelli L, Anderson KC, Tai YT. Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. Br J Haematol. 2010;149:537–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Annunziata CM, Hernandez L, Davis RE, Zingone A, Lamy L, Lam LT, Hurt EM, Shaffer AL, Kuehl WM, Staudt LM. A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression. Blood. 2011;117:2396–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kong D, Yamori T. Advances in development of phosphatidylinositol 3-kinase inhibitors. Curr Med Chem. 2009;16:2839–54.

    Article  CAS  PubMed  Google Scholar 

  37. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC, Chauhan D, Richardson PG, Anderson KC. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107:4053–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, Jakubikova J, Maira SM, Garcia-Echeverria C, Schlossman R, Munshi NC, Richardson PG, Anderson KC, Mitsiades CS. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009;69:5835–42.

    Article  CAS  PubMed  Google Scholar 

  39. Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, Ikeda H, Perrone G, Gorgun G, Patel K, Desai N, Sportelli P, Kapoor S, Vali S, Mukherjee S, Munshi NC, Anderson KC, Raje N. Dual inhibition of Akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound–rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010;9:963–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12:131–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL, Kuehl WM. Classical and/or alternative NF-kappaB pathway activation in multiple myeloma. Blood. 2010;115:3541–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hideshima T, Chauhan D, Kiziltepe T, Ikeda H, Okawa Y, Podar K, Raje N, Protopopov A, Munshi NC, Richardson PG, Carrasco RD, Anderson KC. Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications. Blood. 2009;113:5228–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hideshima T, Neri P, Tassone P, Yasui H, Ishitsuka K, Raje N, Chauhan D, Podar K, Mitsiades C, Dang L, Munshi N, Richardson P, Schenkein D, Anderson KC. MLN120B, a novel IKKβ inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res. 2006;12:5887–94.

    Article  CAS  PubMed  Google Scholar 

  44. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, Mitsiades C, Munshi NC, Richardson PG, Carrasco RD, Anderson KC. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood. 2009;114:1046–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Catley L, Tai YT, Chauhan D, Anderson KC. Perspectives for combination therapy to overcome drug-resistant multiple myeloma. Drug Resist Updat. 2005;8:205–18.

    Article  CAS  PubMed  Google Scholar 

  46. Chauhan D, Singh AV, Brahmandam M, Bianchi G, Podar K, Hideshima T, Munshi N, Richardson P, Palladino MA, Anderson KC. Combination of a novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood. 2008;102:1254.

    Google Scholar 

  47. Singh AV, Palladino MA, Lloyd GK, Potts BC, Chauhan D, Anderson KC. Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br J Haematol. 2010;149:550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, Jiang J, Laidig GJ, Lewis ER, Parlati F, Shenk KD, Smyth MS, Sun CM, Vallone MK, Woo TM, Molineaux CJ, Bennett MK. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383–91.

    Article  CAS  PubMed  Google Scholar 

  49. O’Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, Orlowski RZ. 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;15:7085–91.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Iijima M, Momose I, Ikeda D. TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells. Anticancer Res. 2009;29:977–85.

    CAS  PubMed  Google Scholar 

  51. Sanchez E, Li M, Steinberg JA, Wang C, Shen J, Bonavida B, Li ZW, Chen H, Berenson JR. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br J Haematol. 2010;148:569–81.

    Article  CAS  PubMed  Google Scholar 

  52. Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70:1970–80.

    Article  CAS  PubMed  Google Scholar 

  53. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325:834–40.

    Article  CAS  PubMed  Google Scholar 

  54. Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, Schlossman R, Chauhan D, Munshi NC, Hideshima T, Richon VM, Marks PA, Anderson KC. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood. 2003;101:4055–62.

    Article  CAS  PubMed  Google Scholar 

  55. Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA, Cleveland JL, Giles FJ, McConkey DJ. Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood. 2008;112:2917–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, Sun L, Ricker J, Rizvi S, Oerth C, Atkins B, Fearen I, Anderson K, Siegel D. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma. 2008;49:502–7.

    Article  CAS  PubMed  Google Scholar 

  57. Siegel D, Weber D, Mitsiades CS, Rizvi S, Garcia-Vargas J, Howe J, Reiser D, Anderson KC, Richardson PA. Phase I study of vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2008;102:1270.

    Google Scholar 

  58. Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan D, Munshi NC, Anderson KC. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis of antileukemia activity of histone deacetylase inhibitors. J Biol Chem. 2005;280:26729–34.

    Article  CAS  PubMed  Google Scholar 

  60. Ocio EM, Vilanova D, Atadja P, Maiso P, Crusoe E, Fernandez-Lazaro D, Garayoa M, San-Segundo L, Hernandez-Iglesias T, de Alava E, Shao W, Yao YM, Pandiella A, San-Miguel JF. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010;95:794–803.

    Article  CAS  PubMed  Google Scholar 

  61. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003;115:727–38.

    Article  CAS  PubMed  Google Scholar 

  62. Hideshima H, Bradner JE, Wong JDC, Richardson P, Schreiber SL, Anderson KC. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Kung AL, Davies FE, Morgan G, Akiyama M, Shringarpure R, Munshi NC, Richardson PG, Hideshima T, Chauhan D, Gu X, Bailey C, Joseph M, Libermann TA, Rosen NS, Anderson KC. Antimyeloma activity of heat shock protein-90 inhibition. Blood. 2006;107:1092–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K, Rice J, Barabasz A, Foley B, Ikeda H, Raje N, Kiziltepe T, Yasui H, Enatsu S, Anderson KC. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematological tumors by abrogating signaling via Akt and ERK. Blood. 2009;113:846–855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM. Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA. 1996;93:13931–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS, Kuehl WM. Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood. 1996;88:674–81.

    CAS  PubMed  Google Scholar 

  67. Gabrea A, Bergsagel PL, Chesi M, Shou Y, Kuehl WM. Insertion of excised IgH switch sequences causes overexpression of cyclin D1 in a myeloma tumor cell. Mol Cell. 1999;3:119–23.

    Article  CAS  PubMed  Google Scholar 

  68. Shaughnessy J Jr, Gabrea A, Qi Y, Brents L, Zhan F, Tian E, Sawyer J, Barlogie B, Bergsagel PL, Kuehl M. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood. 2001;98:217–23.

    Article  CAS  PubMed  Google Scholar 

  69. McMillin DW, Delmore J, Negri J, Buon L, Jacobs HM, Laubach J, Jakubikova J, Ooi M, Hayden P, Schlossman R, Munshi NC, Lengauer C, Richardson PG, Anderson KC, Mitsiades CS. Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications. Br J Haematol. 2011;152:420–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H, Shiraishi N, Chauhan D, Munshi NC, Green SR, Anderson KC. 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;106:1042–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Santo L, Vallet S, Hideshima T, Cirstea D, Ikeda H, Pozzi S, Patel K, Okawa Y, Gorgun G, Perrone G, Calabrese E, Yule M, Squires M, Ladetto M, Boccadoro M, Richardson PG, Munshi NC, Anderson KC, Raje N. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene. 2010;29:2325–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gorgun G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, Ikeda H, Bianchi G, Hu Y, Cirstea D, Santo L, Tai YT, Nahar S, Zheng M, Bandi M, Carrasco RD, Raje N, Munshi N, Richardson P, Anderson KC. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010;115:5202–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Santo L, Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, Unitt C, Squires M, Hu Y, Chauhan D, Mahindra A, Munshi NC, Anderson KC, Raje N. Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clin Cancer Res. 2011;17:3259–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Badros AZ, Goloubeva O, Rapoport AP, Ratterree B, Gahres N, Meisenberg B, Takebe N, Heyman M, Zwiebel J, Streicher H, Gocke CD, Tomic D, Flaws JA, Zhang B, Fenton RG. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol. 2005;23:4089–99.

    Article  CAS  PubMed  Google Scholar 

  75. Chauhan D, Velankar M, Brahmandam M, Hideshima T, Podar K, Richardson P, Schlossman R, Ghobrial I, Raje N, Munshi N, Anderson KC. A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 2007;26:2374–80.

    Article  CAS  PubMed  Google Scholar 

  76. Chen S, Dai Y, Pei XY, Grant S. Bim upregulation by histone deacetylase inhibitors mediates interactions with the Bcl-2 antagonist ABT-737: evidence for distinct roles for Bcl-2, Bcl-xL, and Mcl-1. Mol Cell Biol. 2009;29:6149–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Trudel S, Stewart AK, Li Z, Shu Y, Liang SB, Trieu Y, Reece D, Paterson J, Wang D, Wen XY. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res. 2007;13:621–9.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA

    Teru Hideshima & Kenneth C. Anderson

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  1. Teru Hideshima
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  2. Kenneth C. Anderson
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Correspondence to Teru Hideshima.

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Hideshima, T., Anderson, K.C. Novel therapies in MM: from the aspect of preclinical studies. Int J Hematol 94, 344–354 (2011). https://doi.org/10.1007/s12185-011-0917-5

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  • DOI: https://doi.org/10.1007/s12185-011-0917-5

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