The Role of Heat Shock Protein 90 as a Therapeutic Target for Multiple Myeloma

  • Constantine S. Mitsiades
  • Teru Hideshima
  • Nikhil C. Munshi
  • Paul G. Richardson
  • Kenneth C. Anderson
Part of the Contemporary Hematology book series (CH)


Heat shock protein 90 (hsp90) is a molecular chaperone ubiquitously present in eukaryotic cells (as reviewed in Neckers and Ivy,1 Xu and Neckers,2 and Workman et al.3). It interacts intracellularly with a broad range of client proteins and functions to preserve their 3-dimensional (3-D) conformation to a functionally competent state, as well as facilitate their intracellular trafficking.4, The interaction of hsp90 with its client proteins involves formation of a multipro-tein complex whereby binding of ATP to the ATP-binding domain of hsp90 allows it to facilitate the proper folding and conformational stabilization of a target protein. In the absence of this ATP hsp90 interaction, client proteins are more likely to remain unfolded or misfolded and become ubiquitinated, thus leading to their proteasomal degradation. Compared to many other heat shock proteins, hsp90 has the intriguing feature that it interacts with a set of client proteins which include cell surface...


Multiple Myeloma Heat Shock Protein Hsp90 Inhibitor Client Protein Proteasome Inhibitor Bortezomib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Neckers L, Ivy SP. Heat shock protein 90. Curr Opin Oncol 2003;15(6):419–24.PubMedCrossRefGoogle Scholar
  2. 2.
    Xu W Neckers L. Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells. Clin Cancer Res 2007;13(6):1625–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Workman P, Burrows F, Neckers L, Rosen N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci 2007.Google Scholar
  4. 4.
    Powers MV, Workman P. Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 2007.Google Scholar
  5. 5.
    Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107(3):1092–.100.PubMedCrossRefGoogle Scholar
  6. 6.
    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(22): 14374–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Pearl LH, Prodromou C. Structure and mechanism of the Hsp90 molecular chaper-one machinery. Annu Rev Biochem 2006;75:271–94.PubMedCrossRefGoogle Scholar
  8. 8.
    Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001;20(42):5991–6000.PubMedCrossRefGoogle Scholar
  9. 9.
    Hsu JH, Shi Y, Hu L, Fisher M, Franke TF, Lichtenstein A. Role of the AKT kinase in expansion of multiple myeloma clones: Effects on cytokine-dependent prolifera-tive and survival responses. Oncogene 2002;21(9):1391–400.PubMedCrossRefGoogle Scholar
  10. 10.
    Hsu J, Shi Y, Krajewski S, et al. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001;98(9):2853–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Mitsiades CS, Mitsiades NS, McMullan CJ, et 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(3):221–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Hideshima T, Neri P, Tassone P, et al. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res 2006;12(19):5887–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002;277(19):16639–47.PubMedCrossRefGoogle Scholar
  14. 14.
    Davies FE, Dring AM, Li C, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003;102(13):4504–11.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhan F, Hardin J, Kordsmeier B, et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002;99(5):1745–57.PubMedCrossRefGoogle Scholar
  16. 16.
    Tarte K, De Vos J, Thykjaer T, et al. Generation of polyclonal plasmablasts from peripheral blood B cells: A normal counterpart of malignant plasmablasts. Blood 2002;100(4):1113–22.PubMedGoogle Scholar
  17. 17.
    De Vos J, Thykjaer T, Tarte K, et al. Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays. Oncogene 2002;21(44):6848–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J, Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005;106(1):296–303.PubMedCrossRefGoogle Scholar
  19. 19.
    Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23(26):6333–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Mitsiades CS, Mitsiades N, Munshi NC, Anderson KC. Focus on multiple myeloma. Cancer Cell 2004;6(5):439–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101(11):4569–75.PubMedCrossRefGoogle Scholar
  22. 22.
    Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia 2007;21(9):2020–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res 2004;64(4):1546–58.PubMedCrossRefGoogle Scholar
  24. 24.
    Negri J, Mitsiades N, Deng QW, et al. PKC412 is a multi-targeting kinase inhibitor with activity against multiple myeloma in vitro and in vivo. Blood 2005;106(11):75a.Google Scholar
  25. 25.
    Mitsiades CS, Mitsiades N, Rooney M, et al. Anti-tumor activity of KOS-953, a cremo-phor-based formulation of the hsp90 inhibitor 17-AAG. Blood 2004;104(11):660A-1A.Google Scholar
  26. 26.
    Duus J, Bahar HI, Venkataraman G, et al. Analysis of expression of heat shock protein-90 (HSP90) and the effects of HSP90 inhibitor (17-AAG) in multiple myeloma. Leuk Lymphoma 2006;47(7):1369–78.PubMedCrossRefGoogle Scholar
  27. 27.
    Sydor JR, Normant E, Pien CS, et al. Development of 17-allylamino-17-demeth-oxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A 2006;103(46):17408–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Chatterjee M, Jain S, Stuhmer T, et al. STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90 alpha and beta in multiple myeloma cells, which critically contribute to tumor-cell survival. Blood 2007;109(2):720–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demeth-oxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res 2006;12(22):6826–35.PubMedCrossRefGoogle Scholar
  30. 30.
    Davenportel, Moore HE, Dunlop AS, et al. Heat shock protein inhibition is associated with activation of the unfolded protein response (UPR) pathway in myeloma plasma cells. Blood 2007.Google Scholar
  31. 31.
    Mitsiades CS, Mitsiades N, Rooney M, et al. IPI-504: A novel hsp90 inhibitor with in vitro and in vivo antitumor activity. Blood 2004;104(11):660A-A.Google Scholar
  32. 32.
    Mitsiades CS, Richardson PG, Munshi NC, Anderson KC. Inhibition of heat shock proteins: Therapeutic perspectives. Haematol Hematol J 2007;92(6):26–7.Google Scholar
  33. 33.
    Richardson PG, Chanan-Khan AA, Alsina M, et al. Safety and activity of KOS-953 in patients with relapsed refractory multiple myeloma (MM): Interim results of a phase 1 trial. Blood 2005;106(11):109a.Google Scholar
  34. 34.
    Richardson P, Chanan-Khan A, Lonial S, et al A multicenter phase 1 clinical trial of tanespimycin (KOS-953) + bortezomib (BZ): Encouraging activity and manageable toxicity in heavily pre-treated patients with relapsed refractory multiple myeloma (MM). In: Annual Meeting of the American Society of Hematology; 2006;, FL.Google Scholar
  35. 35.
    Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 2006;49(15):4606–15.PubMedCrossRefGoogle Scholar
  36. 36.
    Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF-kappaB and upregula-tion of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: Therapeutic implications. Oncogene 2002;21(37):5673–83.PubMedCrossRefGoogle Scholar
  37. 37.
    Grigorieva I, Thomas X, Epstein J. The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone. Exp Hematol 1998;26(7):597–603.PubMedGoogle Scholar
  38. 38.
    Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: Therapeutic implications. Blood 2007;109(11):4839–45.PubMedCrossRefGoogle Scholar
  39. 39.
    Chiosis G, Neckers L. Tumor selectivity of Hsp90 inhibitors: The explanation remains elusive. ACS Chem Biol 2006;1(5):279–84.PubMedCrossRefGoogle Scholar
  40. 40.
    Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003;425(6956):407–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Aoyagi S, Archer TK. Modulating molecular chaperone Hsp90 functions through reversible acetylation. Trends Cell Biol 2005;15(11):565–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Bali P, Pranpat M, Bradner J, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: A novel basis for antileuke-mia activity of histone deacetylase inhibitors. J Biol Chem 2005;280(29):26729–34.PubMedCrossRefGoogle Scholar
  43. 43.
    Kovacs JJ, Murphy PJ, Gaillard S, et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005 ; 18 (5) : 601–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Murphy PJ, Morishima Y, Kovacs JJ, Yao TP, Pratt WB. Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone. J Biol Chem 2005;280(40):33792–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003;101(10):4055–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of his-tone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A 2004;101(2):540–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Phase I trial with IPI-504 in relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma 2007;7(5):341–2.Google Scholar
  48. 48.
    Siegel D, Jagannath S, Mazumder A, et al. Update on phase I clinical trial of IPI-504, a novel, water-soluble Hsp90 inhibitor, in patients with relapsed/refractory multiple myeloma (MM). Blood 2006;108(11):1022A-A.Google Scholar
  49. 49.
    Jagannath S, Siegel D, Richardson P, et al. Phase I clinical trial of IPI-504, a novel, water-soluble Hsp90 inhibitor, in patients with Relapsed/Refractory multiple myeloma (MM). Blood 2005;106(11):719A-20A.Google Scholar
  50. 50.
    Demetri GD, George S, Morgan JA, et al. Overcoming resistance to tyrosine kinase inhibitors (TKIs) through inhibition of Heat Shock Protein 90 (Hsp90) chaperone function in patients with metastatic GIST: Results of a Phase I Trial of IPI-504, a water-soluble Hsp90 inhibitor. Ejc Suppl 2006;4(12):173.Google Scholar
  51. 51.
    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):4420–7.PubMedCrossRefGoogle Scholar
  52. 52.
    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):2609–17.PubMedCrossRefGoogle Scholar
  53. 53.
    Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100(9):3063–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108(10):3458–64.PubMedCrossRefGoogle Scholar
  55. 55.
    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341(21):1565–71.PubMedCrossRefGoogle Scholar
  56. 56.
    Banerji U, O'Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharma-codynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 2005;23(18):4152–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Grem JL, Morrison G, Guo XD, et al. Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 2005;23(9):1885–93.PubMedCrossRefGoogle Scholar
  58. 58.
    Ramanathan RK, Trump DL, Eiseman JL, et al. Phase I pharmacokinetic-pharma-codynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 2005;11(9):3385–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Goetz MP, Toft D, Reid J, et al. Phase I trial of 17-allylamino-17-demethoxygeldan-amycin in patients with advanced cancer. J Clin Oncol 2005;23(6):1078–87.PubMedCrossRefGoogle Scholar
  60. 60.
    Solit DB, Ivy SP, Kopil C, et al. Phase I trial of 17-allylamino-17-demethoxy-geldanamycin in patients with advanced cancer. Clin Cancer Res 2007;13(6): 1775–82.PubMedCrossRefGoogle Scholar
  61. 61.
    Ramanathan RK, Egorin MJ, Eiseman JL, et al. Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers. Clin Cancer Res 2007;13(6):1769–74.PubMedCrossRefGoogle Scholar
  62. 62.
    Weigel BJ, Blaney SM, Reid JM, et al. A phase I study of 17-allylaminogeldan-amycin in relapsed/refractory pediatric patients with solid tumors: A Children's Oncology Group study. Clin Cancer Res 2007;13(6):1789–93.PubMedCrossRefGoogle Scholar
  63. 63.
    Bagatell R, Gore L, Egorin MJ, et al. Phase I pharmacokinetic and pharmacody-namic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: A pediatric oncology experimental therapeutics investigators consortium study. Clin Cancer Res 2007;13(6):1783–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Porter JR, Ge J, Normant E, et al Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90. Abs Pap Am Chem Soc 2006;231.Google Scholar
  65. 65.
    Peng C, Brain J, Hu YG, et al. IPI-504, a Novel, orally active HSP90 inhibitor, prolongs survival of mice with BCR-ABL T315I CML and B-ALL. Blood 2006;108(11):619A-A.Google Scholar
  66. 66.
    Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 2006;49(15):4606–15.PubMedCrossRefGoogle Scholar
  67. 67.
    Kasibhatla SR, Hong K, Biamonte MA, et al. Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem 2007;50(12):2767–78.PubMedCrossRefGoogle Scholar
  68. 68.
    Zhang L, Fan J, Vu K, et al. 7'-substituted benzothiazolothio- and pyridino-thiazolothio-purines as potent heat shock protein 90 inhibitors. J Med Chem 2006 ; 49 (17) : 5352–62.PubMedCrossRefGoogle Scholar
  69. 69.
    Biamonte MA, Shi J, Hong K, et al. Orally active purine-based inhibitors of the heat shock protein 90. J Med Chem 2006;49(2):817–28.PubMedCrossRefGoogle Scholar
  70. 70.
    Chiosis G. Discovery and development of purine-scaffold Hsp90 inhibitors. Curr Top Med Chem 2006;6(11):1183–91.PubMedCrossRefGoogle Scholar
  71. 71.
    McDonald E, Jones K, Brough PA, Drysdale MJ, Workman P. Discovery and development of pyrazole-scaffold Hsp90 inhibitors. Curr Top Med Chem 2006;6(11):1193–203.PubMedCrossRefGoogle Scholar
  72. 72.
    Ferris DK, Harel-Bellan A, Morimoto RI, Welch WJ, Farrar WL. Mitogen and lymphokine stimulation of heat shock proteins in T lymphocytes. Proc Natl Acad Sci U S A 1988;85(11):3850–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Tsan MF, Gao B. Heat shock protein and innate immunity. Cell Mol Immunol 2004;1(4):274–9.PubMedGoogle Scholar
  74. 74.
    Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C. Intracellular and extracellular functions of heat shock proteins: Repercussions in cancer therapy. J Leukoc Biol 2007;81(1):15–27.PubMedCrossRefGoogle Scholar
  75. 75.
    Bae J, Mitsiades C, Tai YT, et al. Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell. J Immunol 2007;178(12):7730–7.PubMedGoogle Scholar
  76. 76.
    Guo F, Rocha K, Bali P, et al. Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res 2005;65(22):10536–44.PubMedCrossRefGoogle Scholar
  77. 77.
    Hu W, Wu W, Verschraegen CF, et al. Proteomic identification of heat shock protein 70 as a candidate target for enhancing apoptosis induced by farnesyl trans-ferase inhibitor. Proteomics 2003;3(10):1904–11.PubMedCrossRefGoogle Scholar
  78. 78.
    Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003;63(19):6174–7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Constantine S. Mitsiades
    • 1
  • Teru Hideshima
    • 2
  • Nikhil C. Munshi
    • 1
  • Paul G. Richardson
    • 1
  • Kenneth C. Anderson
    • 2
  1. 1.Dana-Farber Cancer InstituteBostonUSA
  2. 2.Department of Medical OncologyJerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA

Personalised recommendations