Multiple myeloma: Implementing signaling pathways and molecular biology in clinical trials

Cancer Biology and Therapy

Volumn 10, Issue 9, 2010, Pages 830-838

  Bazzi, Mouhamad ^a   Badros, Ashraf ^a  

^a UNIVERSITY OF MARYLAND   (United States)

Author keywords

AKT inhibitor; HDAC inhibitor; Heast shock protein HSP90; mTOR; Multiple myeloma; Nuclear factor pathway; Refractory myeloma

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 1 TERT BUTYL 3 [6 (3,5 DIMETHOXYPHENYL) 2 (4 DIETHYLAMINOBUTYLAMINO)PYRIDO[2,3 D]PYRIMIDIN 7 YL]UREA; 3 [4 METHYL 2 (2 OXO 3 INDOLINYLMETHYLIDENYL) 3 PYRROLYL]PROPIONIC ACID; ALTIZUMAB; AMGN 0007; ANTINEOPLASTIC AGENT; AVE 1642; BORTEZOMIB; CARFILZOMIB; DENOSUMAB; DEXAMETHASONE; HEAT SHOCK PROTEIN 90; HISTONE DEACETYLASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IPH 2101; LENALIDOMIDE; MDX 1097; N [[5 [(2 AMINO 3 MERCAPTOPROPYL)AMINO][1,1' BIPHENYL] 2 YL]CARBONYL]METHIONINE METHYL ESTER; PANOBINOSTAT; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PLERIXAFOR; PROTEIN KINASE B; SGN 40; TANESPIMYCIN; TEMSIROLIMUS; UNCLASSIFIED DRUG; VANDETANIB; VATALANIB; VORINOSTAT;

BONE MARROW; CELL MATURATION; CLINICAL TRIAL; DRUG MECHANISM; HUMAN; LOW DRUG DOSE; MOLECULAR BIOLOGY; MULTIPLE MYELOMA; NEUROPATHY; PATHOGENESIS; PLASMA CELL; REVIEW; UNSPECIFIED SIDE EFFECT;

ANTINEOPLASTIC AGENTS; BONE MARROW; CHEMOKINES; CLINICAL TRIALS AS TOPIC; CYTOKINES; EXTRACELLULAR MATRIX PROTEINS; HUMANS; MOLECULAR TARGETED THERAPY; MULTIPLE MYELOMA; PLASMA CELLS; SIGNAL TRANSDUCTION;

EID: 78549257488     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.10.9.13622     Document Type: Review

References (88)

1. Jung D, Giallourakis C, Mostoslavsky R, Alt FW. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 2006; 24:541-70.
2. Batista FD, Harwood NE. The who, how and where of antigen presentation to B cells. Nat Rev Immunol 2009; 9:1527.
3. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity 2007; 27:190-202.
4. Honjo T, Kinoshita K, Muramatsu M. Molecular mechanism of class switch recombination: Linkage with somatic hypermutation. Annu Rev Immunol 2002; 20:165-96. (Pubitemid 34293423)
5. Mitsiades CS, Mitsiades NS, Munshi NC, Richardson PG, Anderson KC. The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: Interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 2006; 42:1564-73.
6. Mitsiades CS, Mitsiades N, Munshi NC, Anderson KC. Focus on multiple myeloma. Cancer Cell 2004; 6:439-44.
7. Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin- 6 secretion. Blood 1993; 82:3712-20.
8. Uchiyama H, Barut BA, Chauhan D, Cannistra SA, Anderson KC. Characterization of adhesion molecules on human myeloma cell lines. Blood 1992; 80:2306-14.
9. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: Clinical applications. Blood 2004; 104:607-18.
10. 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. (Pubitemid 47106630)
11. Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: Therapeutic implications. Blood 2005; 105:1383-95.
12. Jakob C, Sterz J, Zavrski I, Heider U, Kleeberg L, Fleissner C, et al. Angiogenesis in multiple myeloma. Eur J Cancer 2006; 42:1581-90.
13. Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994; 87:503-8.
14. Sezer O, Niemoller K, Eucker J, Jakob C, Kaufmann O, Zavrski I, et al. Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann Hematol 2000; 79:574-7.
15. Bataille R, Chappard D, Marcelli C, Dessauw P, Sany J, Baldet P, et al. Mechanisms of bone destruction in multiple myeloma: The importance of an unbalanced process in determining the severity of lytic bone disease. J Clin Oncol 1989; 7:1909-14. (Pubitemid 20014340)
16. Yaccoby S. Osteoblastogenesis and tumor growth in myeloma. Leuk Lymphoma 2010; 51:213-20.
17. Qiang YW, Shaughnessy JD Jr, Yaccoby S. Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. Blood 2008; 112:374-82.
18. Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH, et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci USA 2004; 101:6122-7.
19. Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA 2001; 98:11581-6.
20. Pomerantz JL, Baltimore D. Two pathways to NFkappaB. Mol Cell 2002; 10:693-5.
21. Li ZW, Chen H, Campbell RA, Bonavida B, Berenson JR. NFkappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 2008; 15:391-9.
22. Chen LF, Greene WC. Shaping the nuclear action of NFkappaB. Nat Rev Mol Cell Biol 2004; 5:392-401.
23. Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, et al. NFkappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 2003; 22:90-7.
24. Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 2003; 9:1136-44. (Pubitemid 36323723)
25. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, et al. Bortezomib induces canonical nuclear factorkappaB activation in multiple myeloma cells. Blood 2009; 114:1046-52.
26. Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 2009; 23:1964-79.
27. Shaughnessy JD, Zhou Y, Haessler J, van Rhee F, Anaissie E, Nair B, et al. TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3. Br J Haematol 2009; 147:347-51.
28. Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007; 21:151-7.
29. Bolick SC, Landowski TH, Boulware D, Oshiro MM, Ohkanda J, Hamilton AD, et al. The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. Leukemia 2003; 17:451-7.
30. Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 2009; 114:3439-47.
31. Jagannath S, Vij R, Stewart K. Final results of PX-171- 003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). J Clin Oncol 2009; 27:15.
32. Niesvizky R, Bensinger W, Vallone M. 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. J Clin Oncol 2009; 27:15.
33. Vij R, Wang M, Orlowski R. PX-171-004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: An efficacy update. [serial online]. J Clin Oncol 2009; 27:15.
34. Badros AZ. Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency, abstract form, ASCO 2010. J Clin Oncol 2010; 28:15.
35. Wolf JL. Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor, abstract form, ASCO 2010. J Clin Oncol 2010; 28:15.
36. Neckers L, Ivy SP. Heat shock protein 90. Curr Opin Oncol 2003; 15:419-24.
37. Isaacs JS, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 2003; 3:213-7. (Pubitemid 37443877)
38. Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem 2002; 277:39858-66.
39. Schneider C, Sepp-Lorenzino L, Nimmesgern E, Ouerfelli O, Danishefsky S, Rosen N, et al. Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90. Proc Natl Acad Sci USA 1996; 93:14536-41.
40. 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; 109:4839-45.
41. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Kung AL, Davies FE, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006; 107:1092-100. (Pubitemid 43156310)
42. Richardson P, Chanan-Khan AA, Lonial S. 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). [serial online]. Blood 2006; 108:406.
43. Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293:1074-80.
44. Villar-Garea A, Esteller M. Histone deacetylase inhibitors: Understanding a new wave of anticancer agents. Int J Cancer 2004; 112:171-8.
45. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5:769-84.
46. Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of bid and production of reactive oxygen species. Proc Natl Acad Sci USA 2001; 98:10833-8.
47. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: The hydroxamic acid derivative LBH589. Clin Cancer Res 2006; 12:634-42. (Pubitemid 43166159)
48. Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003; 101:4055-62. (Pubitemid 36857886)
49. Catley L, Weisberg E, Tai YT, Atadja P, Remiszewski S, Hideshima T, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003; 102:2615-22.
50. Hideshima T, Bradner JE, Chauhan D, Anderson KC. Intracellular protein degradation and its therapeutic implications. Clin Cancer Res 2005; 11:8530-3.
51. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 2004; 10:3839-52. (Pubitemid 38697620)
52. Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, 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.
53. Weber D, Badros AZ, Jagannath S. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood 2008; 12:322.
54. Siegel D. Combined vorinostat, lenilodamide and dexamthasone therapy in patients with relpased/refractory mutiple myeloma: A phase I study. Blood 2009; 114:305.
55. San Miguel JF. A phase IB, multi-center, open-labeel dose-escalation study of oral pnaobinostat (LBH589) and I.V. bortezomib in patients with relapsed multiple myeloma. ASH 2009; 3852.
56. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 2003; 17:590-603.
57. Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr, Mayo MW. Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NFkappaB. Mol Cell Biol 2000; 20:1626-38.
58. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M. Regulation of raf-akt cross-talk. J Biol Chem 2002; 277:31099-106.
59. Romashkova JA, Makarov SS. NFkappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999; 401:86-90. (Pubitemid 129621607)
60. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, et al. 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.
61. Richardson P, Wolf JL. Perifosine in combination with bortezomib and dexamethasone extends progression-free survival and overall survival in patients with relapsed or relapsed/refractory multiple myeloma who were previously treated with bortezomib: Update phase I/II trial results. Blood 2009; 114:1869.
62. Shi Y, Gera J, Hu L, Hsu JH, Bookstein R, Li W, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002; 62:5027-34.
63. Pene F, Claessens YE, Muller O, Viguié F, Mayeux P, Dreyfus F, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002; 21:6587-97. (Pubitemid 35177037)
64. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res 2009; 69:5835-42.
65. Farag SS, Zhang S, Jansak BS, Wang X, Kraut E, Chan K, et al. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk Res 2009; 33:1475-80.
66. Ghobrial IM, Richardson P. Phase II trial of weekly bortezomib in combination with CCI-779 (temsirolimus) in relapsed or relapsed/refractory multiple myeloma. Blood 2009; 114:748.
67. Liu P, Leong T, Quam L, Billadeau D, Kay NE, Greipp P, et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: Analysis of the eastern cooperative oncology group phase III trial. Blood 1996; 88:2699-706.
68. Neri A, Knowles DM, Greco A, McCormick F, Dalla- Favera R. Analysis of RAS oncogene mutations in human lymphoid malignancies. Proc Natl Acad Sci USA 1988; 85:9268-72.
69. De Clercq E. Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100. Mini Rev Med Chem 2005; 5:805-24. (Pubitemid 41167497)
70. Hussein M, Berenson JR, Niesvizky R, Munshi N, Matous J, Sobecks R, et al. A phase 1 multidose study of dacetuzumab (SGN-40; humanized anti- CD40 mAb) in patients with multiple myeloma. Haematologica 2010.
71. Hadari Y, Schlessinger J. FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma. J Clin Invest 2009; 119:1077-9.
72. Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC. Targeting FGFR3 in multiple myeloma: Inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia 2004; 18:962-6.
73. van Zaanen HC, Lokhorst HM, Aarden LA, Rensink HJ, Warnaar SO, van der Lelie J, et al. Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: A phase I dose-escalating study. Br J Haematol 1998; 102:783-90.
74. Descamps G, Gomez-Bougie P, Venot C, Moreau P, Bataille R, Amiot M. A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances bortezomibinduced apoptosis in myeloma cells lacking CD45. Br J Cancer 2009; 100:366-9.
75. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, 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; 5:221-30.
76. Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, et al. An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am J Hematol 2009; 84:650-6.
77. Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003; 97:887-92.
78. Kovacs MJ, Reece DE, Marcellus D, Meyer RM, Mathews S, Dong RP, et al. A phase II study of ZD6474 zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma - NCIC CTG IND.145. Invest New Drugs 2006; 24:529-35.
79. Spenser A. A phase I study of the anti-kapa monoclonal antibody, MDX-1097, in previously treated multiple myeloma patients, abstract form, ASCO 2010.
80. Benson DM. A phase I study of IPH2101, a novel antiinhibitory KIR monoclonal antibody, in patients with multiple myeloam; abstract form, ASCO 2010.
81. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61:3071-6.
82. Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, et al. Bortezomib overcomes cell-adhesion-mediated drug resistance through down-regulation of VLA-4 expression in multiple myeloma. Oncogene 2009; 28:231-42.
83. 2+ is a critical determinant of velcade (PS-341/ bortezomib) cytotoxicity in myeloma cell lines. Cancer Res 2005; 65:3828-36.
84. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 2002; 99:14374-9. (Pubitemid 35257679)
85. Pei XY, Dai Y, Grant S. The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 2003; 17:2036-45.
86. Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 2006; 66:184-91.
87. Richardson P, Wolf J, Jakubowiak A. Phase I/II results of a multicenter trial of perifosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood 2008; 112:870.
88. Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, et al. Blockade of Hsp27 overcomes Bortezomib/Proteazome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003; 63:6174-7. (Pubitemid 37255160)