Novel targets and derived small molecule inhibitors in multiple Myeloma

Current Cancer Drug Targets

Volumn 12, Issue 7, 2012, Pages 797-813

  Podar, Klaus ^a  

^a UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Bone marrow microenvironment; Bortezomib; Carfilzomib; Combination therapy; HDAC inhibitors; Lenalidomide; Multiple myeloma; Pomalidomide; Small molecule inhibitors; Thalidomide

Indexed keywords

6 ACETYL 8 CYCLOPENTYL 5 METHYL 2 [5 (1 PIPERAZINYL) 2 PYRIDINYLAMINO] 8H PYRIDO[2,3 D]PYRIMIDIN 7 ONE; ANTINEOPLASTIC AGENT; BELINOSTAT; BORTEZOMIB; CARFILZOMIB; DACINOSTAT; DELANZOMIB; DEXAMETHASONE; DOVITINIB; ELOTUZUMAB; ENTINOSTAT; ETARACIZUMAB; FLAVOPIRIDOL; FLUINDOSTATIN; GIVINOSTAT; LENALIDOMIDE; MEVINOLIN; NATALIZUMAB; PANOBINOSTAT; POMALIDOMIDE; RESVERATROL; ROMIDEPSIN; SALINOSPORAMIDE A; SIMVASTATIN; SMALL MOLECULE INHIBITOR; THALIDOMIDE; TUBACIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VISMODEGIB; VORINOSTAT;

ANGIOGENESIS; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER RELAPSE; CANCER STEM CELL; CELL CLONE; CELL MATURATION; CELL MEMBRANE; CYTOTOXICITY; DRUG DOSE ESCALATION; DRUG POTENTIATION; EPIGENETICS; EXTRACELLULAR MATRIX; HUMAN; MOLECULARLY TARGETED THERAPY; MULTIPLE MYELOMA; NEUROPATHY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); STROMA CELL; TREATMENT RESPONSE; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC AGENTS; BONE MARROW; CLINICAL TRIALS AS TOPIC; DRUG EVALUATION, PRECLINICAL; HUMANS; MOLECULAR TARGETED THERAPY; MULTIPLE MYELOMA; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84866371772     PISSN: 15680096     EISSN: 18735576     Source Type: Journal    
DOI: 10.2174/156800912802429319     Document Type: Article

References (184)

1. Palumbo, A.; Anderson, K. Multiple myeloma. N. Engl. J. Med. 2011, 364, 1046-1060.
2. Podar, K.; Chauhan, D.; Anderson, K. C. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 2009, 23, 10-24.
3. Adams, J. The proteasome: a suitable antineoplastic target. Nat. Rev. Cancer 2004, 4, 349-360.
4. Chauhan, D.; Li, G.; Shringarpure, R.; Podar, K.; Ohtake, Y.; Hideshima, T.; Anderson, K.C. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003, 63, 6174-6177.
5. Hideshima, T.; Akiyama, M.; Hayashi, T.; Richardson, P.; Schlossman, R.; Chauhan, D.; Anderson, K. C. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood 2003, 101, 703-705.
6. Podar, K.; Gouill, S. L.; Zhang, J.; Opferman, J. T.; Zorn, E.; Tai, Y. T.; Hideshima, T.; Amiot, M.; Chauhan, D.; Harousseau, J. L.; Anderson, K. C. A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene 2008, 27, 721-731.
7. Khan, M. L.; Stewart, A. K. Carfilzomib: a novel secondgeneration proteasome inhibitor. Future Oncol. 2011, 7, 607-612.
8. Anderson, K. C. The 39th David A. Karnofsky Lecture: bench-tobedside translation of targeted therapies in multiple myeloma. J. Clin. Oncol. 2012, 30, 445-452.
9. Vij, R.; Wang, M.; Kaufman, J. L.; Lonial, S.; Jakubowiak, A. J.; Stewart, A. K.; Kukreti, V.; Jagannath, S.; McDonagh, K. T.; Alsina, M.; Bahlis, N. J.; Reu, F. J.; Gabrail, N. Y.; Belch, A.; Matous, J. V.; Lee, P.; Rosen, P.; Sebag, M.; Vesole, D. H.; Kunkel, L. A.; Wear, S. M.; Wong, A. F.; Orlowski, R. Z.; Siegel, D. S. An openlabel, 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, [Epub ahead of print].
10. Chauhan, D.; Singh, A.; Brahmandam, M.; Podar, K.; Hideshima, T.; Richardson, P.; Munshi, N.; Palladino, M. A.; Anderson, K. C. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008, 111, 1654-1664.
11. D'Amato, R. J.; Loughnan, M. S.; Flynn, E.; Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. USA 1994, 91, 4082-4085.
12. Singhal, S.; Mehta, J.; Desikan, R.; Ayers, D.; Roberson, P.; Eddlemon, P.; Munshi, N.; Anaissie, E.; Wilson, C.; Dhodapkar, M.; Zeddis, J.; Barlogie, B. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 1999, 341, 1565-1571.
13. Bartlett, J. B.; Dredge, K.; Dalgleish, A. G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 2004, 4, 314-322.
14. Hideshima, T.; Chauhan, D.; Shima, Y.; Raje, N.; Davies, F. E.; Tai, Y. T.; Treon, S. P.; Lin, B.; Schlossman, R. L.; Richardson, P.; Muller, G.; Stirling, D. I.; Anderson, K. C. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000, 96, 2943-2950.
15. D'Amato, R. J.; Lentzsch, S.; Anderson, K. C.; Rogers, M. S. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin. Oncol. 2001, 28, 597-601.
16. Davies, F. E.; Raje, N.; Hideshima, T.; Lentzsch, S.; Young, G.; Tai, Y. T.; Lin, B.; Podar, K.; Gupta, D.; Chauhan, D.; Treon, S. P.; Richardson, P. G.; Schlossman, R. L.; Morgan, G. J.; Muller, G. W.; Stirling, D. I.; Anderson, K. C. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001, 98, 210-216.
17. Vallet, S.; Witzens-Harig, M.; Jaeger, D.; Podar, K. Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies. Expert. Opin. Pharmacother. 2012, 13, 473-494.
18. Schey, S. A.; Fields, P.; Bartlett, J. B.; Clarke, I. A.; Ashan, G.; Knight, R. D.; Streetly, M.; Dalgleish, A. G. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol. 2004, 22, 3269-3276.
19. Lacy, M. Q.; Hayman, S. R.; Gertz, M. A.; Dispenzieri, A.; Buadi, F.; Kumar, S.; Greipp, P. R.; Lust, J. A.; Russell, S. J.; Dingli, D.; Kyle, R. A.; Fonseca, R.; Bergsagel, P. L.; Roy, V.; Mikhael, J. R.; Stewart, A. K.; Laumann, K.; Allred, J. B.; Mandrekar, S. J.; Rajkumar, S. V. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J. Clin. Oncol. 2009, 27, 5008-5014.
20. Hideshima, T.; Mitsiades, C.; Tonon, G.; Richardson, P. G.; Anderson, K. C. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat. Rev. Cancer 2007, 7, 585-598.
21. Podar, K.; Anderson, K. C. Emerging therapies targeting tumor vasculature in multiple myeloma and other hematologic and solid malignancies. Curr. Cancer Drug Targets 2011, 11, 1005-1024.
22. Carrasco, D. R.; Sukhdeo, K.; Protopopova, M.; Sinha, R.; Enos, M.; Carrasco, D. E.; Zheng, M.; Mani, M.; Henderson, J.; Pinkus, G. S.; Munshi, N.; Horner, J.; Ivanova, E. V.; Protopopov, A.; Anderson, K. C.; Tonon, G.; DePinho, R. A. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 2007, 11, 349-360.
23. Lee, A. H.; Iwakoshi, N. N.; Anderson, K. C.; Glimcher, L. H. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl. Acad. Sci. USA 2003, 100, 9946-9951.
24. Tashiro, E.; Hironiwa, N.; Kitagawa, M.; Futamura, Y.; Suzuki, S.; Nishio, M.; Imoto, M. Trierixin, a novel Inhibitor of ER stressinduced XBP1 activation from Streptomyces sp. 1. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. (Tokyo) 2007, 60, 547-553.
25. Bae, J.; Carrasco, R.; Lee, A. H.; Prabhala, R.; Tai, Y. T.; Anderson, K. C.; Munshi, N. C. Identification of novel myelomaspecific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma. Leukemia 2012, 25, 1610-1619.
26. Mimura, N.; Fulciniti, M.; Gorgun, G.; Tai, Y. T.; Cirstea, D.; Santo, L.; Hu, Y.; Fabre, C.; Minami, J.; Ohguchi, H.; Kiziltepe, T.; Ikeda, H.; Kawano, Y.; French, M.; Blumenthal, M.; Tam, V.; Kertesz, N.L.; Malyankar, U. M.; Hokenson, M.; Pham, T.; Zeng, Q.; Patterson, J. B.; Richardson, P. G.; Munshi, N. C.; Anderson, K. C. Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. Blood 2012, [Epub ahead of print].
27. D'Costa, K.; Emslie, D.; Metcalf, D.; Smyth, G. K.; Karnowski, A.; Kallies, A.; Nutt, S. L.; Corcoran, L. M. Blimp1 is limiting for transformation in a mouse plasmacytoma model. Blood 2009, 113, 5911-5919.
28. Shaffer, A. L.; Emre, N. C.; Lamy, L.; Ngo, V. N.; Wright, G.; Xiao, W.; Powell, J.; Dave, S.; Yu, X.; Zhao, H.; Zeng, Y.; Chen, B.; Epstein, J.; Staudt, L. M. IRF4 addiction in multiple myeloma. Nature 2008, 454, 226-231.
29. Matsui, W.; Huff, C. A.; Wang, Q.; Malehorn, M. T.; Barber, J.; Tanhehco, Y.; Smith, B. D.; Civin, C. I.; Jones, R. J. Characterization of clonogenic multiple myeloma cells. Blood 2004, 103, 2332-2336.
30. Peacock, C. D.; Wang, Q.; Gesell, G. S.; Corcoran-Schwartz, I. M.; Jones, E.; Kim, J.; Devereux, W. L.; Rhodes, J. T.; Huff, C. A.; Beachy, P. A.; Watkins, D. N.; Matsui, W. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl. Acad. Sci. USA 2007, 104, 4048-4053.
31. Matsui, W.; Wang, Q.; Barber, J. P.; Brennan, S.; Smith, B. D.; Borrello, I.; McNiece, I.; Lin, L.; Ambinder, R. F.; Peacock, C.; Watkins, D. N.; Huff, C. A.; Jones, R. J. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008, 68, 190-197.
32. Smadja, N. V.; Fruchart, C.; Isnard, F.; Louvet, C.; Dutel, J. L.; Cheron, N.; Grange, M. J.; Monconduit, M.; Bastard, C. Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia 1998, 12, 960-969.
33. Debes-Marun, C. S.; Dewald, G. W.; Bryant, S.; Picken, E.; Santana-Davila, R.; Gonzalez-Paz, N.; Winkler, J. M.; Kyle, R. A.; Gertz, M. A.; Witzig, T. E.; Dispenzieri, A.; Lacy, M. Q.; Rajkumar, S. V.; Lust, J. A.; Greipp, P. R.; Fonseca, R. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia 2003, 17, 427-436.
34. Carrasco, D. R.; Tonon, G.; Huang, Y.; Zhang, Y.; Sinha, R.; Feng, B.; Stewart, J. P.; Zhan, F.; Khatry, D.; Protopopova, M.; Protopopov, A.; Sukhdeo, K.; Hanamura, I.; Stephens, O.; Barlogie, B.; Anderson, K. C.; Chin, L.; Shaughnessy, J. D. Jr.; Brennan, C.; Depinho, R. A. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006, 9, 313-325.
35. Zhan, F.; Huang, Y.; Colla, S.; Stewart, J. P.; Hanamura, I.; Gupta, S.; Epstein, J.; Yaccoby, S.; Sawyer, J.; Burington, B.; Anaissie, E.; Hollmig, K.; Pineda-Roman, M.; Tricot, G.; van Rhee, F.; Walker, R.; Zangari, M.; Crowley, J.; Barlogie, B.; Shaughnessy, J.D. Jr. The molecular classification of multiple myeloma. Blood 2006, 108, 2020-2028.
36. Shaughnessy, J. D. Jr.; Zhan, F.; Burington, B. E.; Huang, Y.; Colla, S.; Hanamura, I.; Stewart, J. P.; Kordsmeier, B.; Randolph, C.; Williams, D. R.; Xiao, Y.; Xu, H.; Epstein, J.; Anaissie, E.; Krishna, S. G.; Cottler-Fox, M.; Hollmig, K.; Mohiuddin, A.; Pineda-Roman, M.; Tricot, G.; van Rhee, F.; Sawyer, J.; Alsayed, Y.; Walker, R.; Zangari, M.; Crowley, J.; Barlogie, B. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007, 109, 2276-2284.
37. Bergsagel, P. L.; Kuehl, W. M. Molecular pathogenesis and a consequent classification of multiple myeloma. J. Clin. Oncol. 2005, 23, 6333-6338.
38. Hideshima, T.; Bergsagel, P. L.; Kuehl, W. M.; Anderson, K. C. Advances in biology of multiple myeloma: clinical applications. Blood 2004, 104, 607-618.
39. Fonseca, R.; Bergsagel, P. L.; Drach, J.; Shaughnessy, J.; Gutierrez, N.; Stewart, A. K.; Morgan, G.; Van Ness, B.; Chesi, M.; Minvielle, S.; Neri, A.; Barlogie, B.; Kuehl, W. M.; Liebisch, P.; Davies, F.; Chen-Kiang, S.; Durie, B. G.; Carrasco, R.; Sezer, O.; Reiman, T.; Pilarski, L.; Avet-Loiseau, H. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009, 23, 2210-2221.
40. Dewald, G. W.; Therneau, T.; Larson, D.; Lee, Y.K.; Fink, S.; Smoley, S.; Paternoster, S.; Adeyinka, A.; Ketterling, R.; van Dyke, D. L.; Fonseca, R.; Kyle, R. Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma. Blood 2005, 106, 3553-3558.
41. Chesi, M.; Nardini, E.; Lim, R. S.; Smith, K. D.; Kuehl, W. M.; Bergsagel, P. L. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 1998, 92, 3025-3034.
42. Hurt, E. M.; Wiestner, A.; Rosenwald, A.; Shaffer, A. L.; Campo, E.; Grogan, T.; Bergsagel, P. L.; Kuehl, W. M.; Staudt, L. M. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell. 2004, 5, 191-199.
43. Trudel, S.; Ely, S.; Farooqi, Y.; Affer, M.; Robbiani, D. F.; Chesi, M.; Bergsagel, P. L. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 2004, 103, 3521-3528.
44. Trudel, S.; Li, Z.H.; Wei, E.; Wiesmann, M.; Chang, H.; Chen, C.; Reece, D.; Heise, C.; Stewart, A. K. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 2005, 105, 2941-2948.
45. Xin, X.; Abrams, T. J.; Hollenbach, P. W.; Rendahl, K. G.; Tang, Y.; Oei, Y. A.; Embry, M. G.; Swinarski, D. E.; Garrett, E. N.; Pryer, N. K.; Trudel, S.; Jallal, B.; Mendel, D. B.; Heise, C. C. CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin. Cancer Res. 2006, 12, 4908-4915.
46. Krejci, P.; Murakami, S.; Prochazkova, J.; Trantirek, L.; Chlebova, K.; Ouyang, Z.; Aklian, A.; Smutny, J.; Bryja, V.; Kozubik, A.; Wilcox, W. R. 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, 20644-20653.
47. Trudel, S.; Stewart, A. K.; Rom, E.; Wei, E.; Li, Z. H.; Kotzer, S.; Chumakov, I.; Singer, Y.; Chang, H.; Liang, S.B.; Yayon, A. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 2006, 107, 4039-4046.
48. Shou, Y.; Martelli, M. L.; Gabrea, A.; Qi, Y.; Brents, L. A.; Roschke, A.; Dewald, G.; Kirsch, I. R.; Bergsagel, P. L.; Kuehl, W. M. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc. Natl. Acad. Sci. USA 2000, 97, 228-233.
49. Cheung, W. C.; Kim, J. S.; Linden, M.; Peng, L.; Van Ness, B.; Polakiewicz, R. D.; Janz, S. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. J. Clin. Invest. 2004, 113, 1763-1773.
50. Chesi, M.; Robbiani, D. F.; Sebag, M.; Chng, W. J.; Affer, M.; Tiedemann, R.; Valdez, R.; Palmer, S. E.; Haas, S. S.; Stewart, A. K.; Fonseca, R.; Kremer, R.; Cattoretti, G. Bergsagel, P. L. AIDdependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell. 2008, 13, 167-180.
51. Baudino, T. A.; McKay, C.; Pendeville-Samain, H.; Nilsson, J. A.; Maclean, K. H.; White, E. L.; Davis, A. C.; Ihle, J. N.; Cleveland, J. L. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev. 2002, 16, 2530-2543.
52. Knies-Bamforth, U. E.; Fox, S. B.; Poulsom, R.; Evan, G. I.; Harris, A. L. c-Myc interacts with hypoxia to induce angiogenesis in vivo by a vascular endothelial growth factor-dependent mechanism. Cancer Res. 2004, 64, 6563-6570.
53. Mezquita, P.; Parghi, S. S.; Brandvold, K. A.; Ruddell, A. Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation. Oncogene 2005, 24, 889-901.
54. Podar, K.; Anderson, K. C. A therapeutic role for targeting c- Myc/Hif-1-dependent signaling pathways. Cell Cycle 2010, 9, 1722-1728.
55. Zhang, J.; Sattler, M.; Tonon, G.; Grabher, C.; Lababidi, S.; Zimmerhackl, A.; Raab, M. S.; Vallet, S.; Zhou, Y.; Cartron, M. A.; Hideshima, T.; Tai, Y. T.; Chauhan, D.; Anderson, K. C.; Podar, K. Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. Cancer Res. 2009, 69, 5082-5090.
56. Kiessling, A.; Wiesinger, R.; Sperl, B.; Berg, T. Selective inhibition of c-Myc/Max dimerization by a pyrazolo[1,5- a]pyrimidine. Chem. Med. Chem. 2007, 2, 627-630.
57. Mo, H.; Henriksson, M. Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation. Proc. Natl. Acad. Sci. USA 2006, 103, 6344-6349.
58. Mo, H.; Vita, M.; Crespin, M.; Henriksson, M. Myc overexpression enhances apoptosis induced by small molecules. Cell Cycle 2006, 5, 2191-2194.
59. Delmore, J. E.; Issa, G. C.; Lemieux, M. E.; Rahl, P. B.; Shi, J.; Jacobs, H. M.; Kastritis, E.; Gilpatrick, T.; Paranal, R. M.; Qi, J.; Chesi, M.; Schinzel, A. C.; McKeown, M. R.; Heffernan, T. P.; Vakoc, C. R.; Bergsagel, P. L.; Ghobrial, I. M.; Richardson, P. G.; Young, R. A.; Hahn, W. C.; Anderson, K. C.; Kung, A. L.; Bradner, J. E.; Mitsiades, C. S. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146, 904-917.
60. Podar, K.; Richardson, P. G.; Hideshima, T.; Chauhan, D.; Anderson, K. C. The malignant clone and the bone-marrow environment. Best Pract. Res. Clin. Haematol. 2007, 20, 597-612.
61. Chim, C. S.; Kwong, Y. L.; Liang, R. Gene hypermethylation in multiple myeloma: lessons from a cancer pathway approach. Clin. Lymphoma Myeloma 2008, 8, 331-339.
62. Smith, E. M.; Boyd, K.; Davies, F. E. The potential role of epigenetic therapy in multiple myeloma. Br. J. Haematol. 2010, 148, 702-713.
63. Mitsiades, N.; Mitsiades, C. S.; Richardson, P. G.; McMullan, C.; Poulaki, V.; Fanourakis, G.; Schlossman, R.; Chauhan, D.; Munshi, N. C.; Hideshima, T.; Richon, V. M.; Marks, P. A.; Anderson, K. C. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003, 101, 4055-4062.
64. Catley, L.; Weisberg, E.; Tai, Y. T.; Atadja, P.; Remiszewski, S.; Hideshima, T.; Mitsiades, N.; Shringarpure, R.; LeBlanc, R.; Chauhan, D.; Munshi, N. C.; Schlossman, R.; Richardson, P.; Griffin, J.; Anderson, K.C. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003, 102, 2615-2622.
65. Catley, L.; Weisberg, E.; Kiziltepe, T.; Tai, Y. T.; Hideshima, T.; Neri, P.; Tassone, P.; Atadja, P.; Chauhan, D.; Munshi, N. C.; Anderson, K. C. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006, 108, 3441-3449.
66. Maiso, P.; Carvajal-Vergara, X.; Ocio, E. M.; Lopez-Perez, R.; Mateo, G.; Gutierrez, N.; Atadja, P.; Pandiella, A.; San-Miguel, J. F. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res. 2006, 66, 5781-5789.
67. Feng, R.; Oton, A.; Mapara, M. Y.; Anderson, G.; Belani, C.; Lentzsch, S. The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. Br. J. Haematol. 2007, 139, 385-397.
68. Miller, C. P.; Ban, K.; Dujka, M. E.; McConkey, D. J.; Munsell, M.; Palladino, M.; Chandra, J. NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 2007, 110, 267-277.
69. Khan, S. B.; Maududi, T.; Barton, K.; Ayers, J.; Alkan, S. Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma. Br. J. Haematol. 2004, 125, 156-161.
70. Hideshima, T.; Bradner, J. E.; Wong, J.; Chauhan, D.; Richardson, P.; Schreiber, S. L.; Anderson, K. C. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc. Natl. Acad. Sci. USA 2005, 102, 8567-8572.
71. Fonseca, R.; Bailey, R. J.; Ahmann, G. J.; Rajkumar, S. V.; Hoyer, J. D.; Lust, J. A.; Kyle, R. A.; Gertz, M. A.; Greipp, P. R.; Dewald, G. W. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002, 100, 1417-1424.
72. Zhan, F.; Hardin, J.; Kordsmeier, B.; Bumm, K.; Zheng, M.; Tian, E.; Sanderson, R.; Yang, Y.; Wilson, C.; Zangari, M.; Anaissie, E.; Morris, C.; Muwalla, F.; van Rhee, F.; Fassas, A.; Crowley, J.; Tricot, G.; Barlogie, B.; Shaughnessy, J. Jr. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002, 99, 1745-1757.
73. Keats, J. J.; Reiman, T.; Belch, A. R.; Pilarski, L. M. Ten years and counting: so what do we know about t(4;14)(p16;q32) multiple myeloma. Leuk. Lymphoma 2006, 47, 2289-2300.
74. Chng, W. J.; Glebov, O.; Bergsagel, P. L.; Kuehl, W. M. Genetic events in the pathogenesis of multiple myeloma. Best Pract. Res. Clin. Haematol. 2007, 20, 571-596.
75. Ribatti, D.; Vacca, A. The role of microenvironment in tumor angiogenesis. Genes Nutr. 2008, 3, 29-34.
76. Roodman, G. D. Targeting the bone microenvironment in multiple myeloma. J. Bone Miner. Metab. 2010, 28, 244-250.
77. Hazlehurst, L. A.; Landowski, T. H.; Dalton, W. S. Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene 2003, 22, 7396-7402.
78. Damiano, J. S.; Cress, A. E.; Hazlehurst, L. A.; Shtil, A. A.; Dalton, W. S. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999, 93, 1658-1667.
79. Hazlehurst, L. A.; Damiano, J. S.; Buyuksal, I.; Pledger, W. J.; Dalton, W. S. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 2000, 19, 4319-4327.
80. Vacca, A.; Ribatti, D.; Roncali, L.; Dammacco, F. Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies. Leuk. Lymphoma 1995, 20, 27-38.
81. Noborio-Hatano, K.; Kikuchi, J.; Takatoku, M.; Shimizu, R.; Wada, T.; Ueda, M.; Nobuyoshi, M.; Oh, I.; Sato, K.; Suzuki, T.; Ozaki, K.; Mori, M.; Nagai, T.; Muroi, K.; Kano, Y.; Furukawa, Y.; Ozawa, K. Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene 2009, 28, 231-242.
82. Mori, Y.; Shimizu, N.; Dallas, M.; Niewolna, M.; Story, B.; Williams, P. J.; Mundy, G.R.; Yoneda, T. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 2004, 104, 2149-2154.
83. Olson, D. L.; Burkly, L. C.; Leone, D. R.; Dolinski, B. M.; Lobb, R. R. Anti-alpha4 integrin monoclonal antibody inhibits multiple myeloma growth in a murine model. Mol. Cancer Ther. 2005, 4, 91-99.
84. Podar, K.; Zimmerhackl, A.; Fulciniti, M.; Tonon, G.; Hainz, U.; Tai, Y. T.; Vallet, S.; Halama, N.; Jager, D.; Olson, D. L.; Sattler, M.; Chauhan, D.; Anderson, K. C. The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. Br. J. Haematol. 2011, 155, 438-448.
85. Vacca, A.; Ria, R.; Presta, M.; Ribatti, D.; Iurlaro, M.; Merchionne, F.; Tanghetti, E.; Dammacco, F. Alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells. Exp. Hematol. 2001, 29, 993-1003.
86. Boissy, P.; Andersen, T. L.; Abdallah, B. M.; Kassem, M.; Plesner, T.; Delaisse, J.M. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res. 2005, 65, 9943-9952.
87. Tai, Y. T.; Dillon, M.; Song, W.; Leiba, M.; Li, X. F.; Burger, P.; Lee, A. I.; Podar, K.; Hideshima, T.; Rice, A. G.; van Abbema, A.; Jesaitis, L.; Caras, I.; Law, D.; Weller, E.; Xie, W.; Richardson, P.; Munshi, N. C.; Mathiot, C.; Avet-Loiseau, H.; Afar, D. E.; Anderson, K. C. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibodydependent cellular cytotoxicity in the bone marrow milieu. Blood 2008, 112, 1329-1337.
88. Sekimoto, E.; Ozaki, S.; Ohshima, T.; Shibata, H.; Hashimoto, T.; Abe, M.; Kimura, N.; Hattori, K.; Kawai, S.; Kinoshita, Y.; Yamada-Okabe, H.; Tsuchiya, M.; Matsumoto, T. A single-chain Fv diabody against human leukocyte antigen-A molecules specifically induces myeloma cell death in the bone marrow environment. Cancer Res. 2007, 67, 1184-1192.
89. Yang, J.; Qian, J.; Wezeman, M.; Wang, S.; Lin, P.; Wang, M.; Yaccoby, S.; Kwak, L. W.; Barlogie, B.; Yi, Q. Targeting beta2- microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell 2006, 10, 295-307.
90. Hideshima, T.; Richardson, P.; Chauhan, D.; Palombella, V. J.; Elliott, P. J.; Adams, J.; Anderson, K. C. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001, 61, 3071-3076.
91. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 2002, 296, 1655-1657.
92. Brunet, A.; Bonni, A.; Zigmond, M. J.; Lin, M. Z.; Juo, P.; Hu, L. S.; Anderson, M. J.; Arden, K. C.; Blenis, J.; Greenberg, M. E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999, 96, 857-868.
93. Madrid, L. V.; Wang, C. Y.; Guttridge, D. C.; Schottelius, A. J.; Baldwin, A. S. Jr.; Mayo, M. W. Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol. Cell Biol. 2000, 20, 1626-1638.
94. Madrid, L. V.; Mayo, M. W.; Reuther, J. Y.; Baldwin, A. S. Jr. Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J. Biol. Chem. 2001, 276, 18934-18940.
95. Brazil, D. P.; Park, J.; Hemmings, B. A. PKB binding proteins. Getting in on the Akt. Cell 2002, 111, 293-303.
96. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489-501.
97. Akiyama, M.; Hideshima, T.; Hayashi, T.; Tai, Y. T.; Mitsiades, C. S.; Mitsiades, N.; Chauhan, D.; Richardson, P.; Munshi, N. C.; Anderson, K. C. Nuclear factor-kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Res. 2003, 63, 18-21.
98. Puthier, D.; Bataille, R.; Amiot, M. IL-6 up-regulates mcl-1 in human myeloma cells through JAK / STAT rather than ras / MAP kinase pathway. Eur. J. Immunol. 1999, 29, 3945-3950.
99. Hideshima, T.; Nakamura, N.; Chauhan, D.; Anderson, K. C. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001, 20, 5991-6000.
100. Hideshima, T.; Catley, L.; Yasui, H.; Ishitsuka, K.; Raje, N.; Mitsiades, C.; Podar, K.; Munshi, N. C.; Chauhan, D.; Richardson, P. G.; Anderson, K. C. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and In vivo cytotoxicity in human multiple myeloma (MM) cells. Blood 2005, 106, 128.
101. Tai, Y. T.; Fulciniti, M.; Hideshima, T.; Song, W.; Leiba, M.; Li, X. F.; Rumizen, M.; Burger, P.; Morrison, A.; Podar, K.; Chauhan, D.; Tassone, P.; Richardson, P.; Munshi, N. C.; Ghobrial, I. M.; Anderson, K. C. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood 2007, 110, 1656-1663.
102. Hideshima, T.; Catley, L.; Raje, N.; Chauhan, D.; Podar, K.; Mitsiades, C.; Tai, Y. T.; Vallet, S.; Kiziltepe, T.; Ocio, E.; Ikeda, H.; Okawa, Y.; Hideshima, H.; Munshi, N. C.; Yasui, H.; Richardson, P. G.; Anderson, K. C. Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br. J. Haematol. 2007, 138, 783-791.
103. Huston, A.; Leleu, X.; Jia, X.; Moreau, A. S.; Ngo, H. T.; Runnels, J.; Anderson, J.; Alsayed, Y.; Roccaro, A.; Vallet, S.; Hatjiharissi, E.; Tai, Y. T.; Sportelli, P.; Munshi, N.; Richardson, P.; Hideshima, T.; Roodman, D. G.; Anderson, K. C.; Ghobrial, I. M. Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment. Clin. Cancer Res. 2008, 14, 865-874.
104. Shi, Y.; Gera, J.; Hu, L.; Hsu, J. H.; Bookstein, R.; Li, W.; Lichtenstein, A. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 2002, 62, 5027-5034.
105. Frost, P.; Moatamed, F.; Hoang, B.; Shi, Y.; Gera, J.; Yan, H.; Frost, P.; Gibbons, J.; Lichtenstein, A. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004, 104, 4181-4187.
106. Raje, N.; Kumar, S.; Hideshima, T.; Ishitsuka, K.; Chauhan, D.; Mitsiades, C.; Podar, K.; Le Gouill, S.; Richardson, P.; Munshi, N. C.; Stirling, D. I.; Antin, J. H.; Anderson, K. C. Combination of the mTOR inhibitor Rapamycin and RevlimidTM(CC-5013) has synergistic activity in multiple myeloma. Blood 2004, 104, 4188-4193
107. Francis, L. K.; Alsayed, Y.; Leleu, X.; Jia, X.; Singha, U. K.; Anderson, J.; Timm, M.; Ngo, H.; Lu, G.; Huston, A.; Ehrlich, L. A.; Dimmock, E.; Lentzsch, S.; Hideshima, T.; Roodman, G. D.; Anderson, K. C.; Ghobrial, I. M. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino- 17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin. Cancer Res. 2006, 12, 6826-6835.
108. Hideshima, T.; Podar, K.; Chauhan, D.; Anderson, K. C. Cytokines and signal transduction. Best Pract. Res. Clin. Haematol. 2005, 18, 509-524.
109. Neri, A.; Murphy, J. P.; Cro, L.; Ferrero, D.; Tarella, C.; Baldini, L.; Dalla-Favera, R. Ras oncogene mutation in multiple myeloma. J. Exp. Med. 1989, 170, 1715-1725.
110. Liu, P.; Leong, T.; Quam, L.; Billadeau, D.; Kay, N. E.; Greipp, P.; Kyle, R. A.; Oken, M. M.; Van Ness, B. Activating mutations of Nand K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 1996, 88, 2699-2706.
111. Tiedemann, R. E.; Gonzalez-Paz, N.; Kyle, R. A.; Santana-Davila, R.; Price-Troska, T.; Van Wier, S. A.; Chng, W. J.; Ketterling, R. P.; Gertz, M. A.; Henderson, K.; Greipp, P. R.; Dispenzieri, A.; Lacy, M. Q.; Rajkumar, S. V.; Bergsagel, P. L.; Stewart, A. K.; Fonseca, R. Genetic aberrations and survival in plasma cell leukemia. Leukemia 2008, 22, 1044-1052.
112. Martin, P.; Santon, A.; Garcia-Cosio, M.; Bellas, C. RAS mutations are uncommon in multiple myeloma and other monoclonal gammopathies. Int. J. Oncol. 2005, 27, 1023-1028.
113. Kato, K.; Cox, A. D.; Hisaka, M. M.; Graham, S. M.; Buss, J. E.; Der, C. J. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc. Natl. Acad. Sci. USA 1992, 89, 6403-6407.
114. Bolick, S. C.; Landowski, T. H.; Boulware, D.; Oshiro, M. M.; Ohkanda, J.; Hamilton, A. D.; Sebti, S. M.; Dalton, W. S. The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. Leukemia 2003, 17, 451-457.
115. Ochiai, N.; Uchida, R.; Fuchida, S.; Okano, A.; Okamoto, M.; Ashihara, E.; Inaba, T.; Fujita, N.; Matsubara, H.; Shimazaki, C. Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro. Blood 2003, 102, 3349-3353.
116. Beaupre, D. M.; Cepero, E.; Obeng, E. A.; Boise, L. H.; Lichtenheld, M.G. R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. Mol. Cancer Ther. 2004, 3, 179-186.
117. Cortes, J.; Albitar, M.; Thomas, D.; Giles, F.; Kurzrock, R.; Thibault, A.; Rackoff, W.; Koller, C.; O'Brien, S.; Garcia-Manero, G.; Talpaz, M.; Kantarjian, H. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003, 101, 1692-1697.
118. Alsina, M.; Fonseca, R.; Wilson, E. F.; Belle, A. N.; Gerbino, E.; Price-Troska, T.; Overton, R. M.; Ahmann, G.; Bruzek, L. M.; Adjei, A. A.; Kaufmann, S. H.; Wright, J. J.; Sullivan, D.; Djulbegovic, B.; Cantor, A. B.; Greipp, P. R.; Dalton, W. S.; Sebti, S. M. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004, 103, 3271-3277.
119. Annunziata, C. M.; Hernandez, L.; Davis, R. E.; Zingone, A.; Lamy, L.; Lam, L. T.; Hurt, E. M.; Shaffer, A. L.; Kuehl, W. M.; Staudt, L. M. A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression. Blood 2010, 117, 2396-2404.
120. Karin, M.; Greten, F. R. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 2005, 5, 749-759.
121. Annunziata, C. M.; Davis, R. E.; Demchenko, Y.; Bellamy, W.; Gabrea, A.; Zhan, F.; Lenz, G.; Hanamura, I.; Wright, G.; Xiao, W.; Dave, S.; Hurt, E. M.; Tan, B.; Zhao, H.; Stephens, O.; Santra, M.; Williams, D. R.; Dang, L.; Barlogie, B.; Shaughnessy, J. D., Jr.; Kuehl, W. M.; Staudt, L. M. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007, 12, 115-130.
122. Keats, J. J.; Fonseca, R.; Chesi, M.; Schop, R.; Baker, A.; Chng, W. J.; Van Wier, S.; Tiedemann, R.; Shi, C. X.; Sebag, M.; Braggio, E.; Henry, T.; Zhu, Y. X.; Fogle, H.; Price-Troska, T.; Ahmann, G.; Mancini, C.; Brents, L. A.; Kumar, S.; Greipp, P.; Dispenzieri, A.; Bryant, B.; Mulligan, G.; Bruhn, L.; Barrett, M.; Valdez, R.; Trent, J.; Stewart, A. K.; Carpten, J.; Bergsagel, P. L. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007, 12, 131-144.
123. Mitsiades, N.; Mitsiades, C. S.; Poulaki, V.; Chauhan, D.; Richardson, P. G.; Hideshima, T.; Munshi, N. C.; Treon, S. P.; Anderson, K. C. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002, 99, 4525-4530.
124. Hayashi, T.; Hideshima, T.; Nguyen, A. N.; Munoz, O.; Podar, K.; Hamasaki, M.; Ishitsuka, K.; Yasui, H.; Richardson, P.; Chakravarty, S.; Murphy, A.; Chauhan, D.; Higgins, L. S.; Anderson, K. C. Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin. Cancer Res. 2004, 10, 7540-7546.
125. Hideshima, T.; Chauhan, D.; Hayashi, T.; Podar, K.; Akiyama, M.; Mitsiades, C.; Mitsiades, N.; Gong, B.; Bonham, L.; de Vries, P.; Munshi, N.; Richardson, P.G.; Singer, J.W. Anderson, K.C. Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. Cancer Res. 2003, 63, 8428-8436.
126. Ito, K.; Nakazato, T.; Xian, M. J.; Yamada, T.; Hozumi, N.; Murakami, A.; Ohigashi, H.; Ikeda, Y.; Kizaki, M. 1'- acetoxychavicol acetate is a novel nuclear factor kappaB inhibitor with significant activity against multiple myeloma in vitro and in vivo. Cancer Res. 2005, 65, 4417-4424.
127. Hideshima, T.; Chauhan, D.; Richardson, P.; Mitsiades, C.; Mitsiades, N.; Hayashi, T.; Munshi, N.; Dang, L.; Castro, A.; Palombella, V.; Adams, J.; Anderson, K.C. NF-kappa B as a therapeutic target in multiple myeloma. J. Biol. Chem. 2002, 277, 16639-16647.
128. 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, K. C. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin. Cancer Res. 2006, 12, 5887-5894.
129. Taga, T.; Hibi, M.; Hirata, Y.; Yamasaki, K.; Yasukawa, K.; Matsuda, T.; Hirano, T.; Kishimoto, T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 1989, 58, 573-581.
130. Nishimoto, N.; Ogata, A.; Shima, Y.; Tani, Y.; Ogawa, H.; Nakagawa, M.; Sugiyama, H.; Yoshizaki, K.; Kishimoto, T. Oncostatin M. leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130. J. Exp. Med. 1994, 179, 1343-1347.
131. Matsuda, T.; Fukada, T.; Takahashi-Tezuka, M.; Okuyama, Y.; Fujitani, Y.; Hanazono, Y.; Hirai, H.; Hirano, T. Activation of Fes tyrosine kinase by gp130, an interleukin-6 family cytokine signal transducer, and their association. J. Biol. Chem. 1995, 270, 11037-11039.
132. Kurth, I.; Horsten, U.; Pflanz, S.; Dahmen, H.; Kuster, A.; Grotzinger, J.; Heinrich, P. C.; Muller-Newen, G. Activation of the signal transducer glycoprotein 130 by both IL-6 and IL-11 requires two distinct binding epitopes. J. Immunol. 1999, 162, 1480-1487.
133. Zhong, Z.; Wen, Z.; Darnell, J. E. Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994, 264, 95-98.
134. Hamasaki, M.; Hideshima, T.; Tassone, P.; Neri, P.; Ishitsuka, K.; Yasui, H.; Shiraishi, N.; Raje, N.; Kumar, S.; Picker, D. H.; Jacob, G. S.; Richardson, P.G.; Munshi, N. C.; Anderson, K. C. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2- propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo. Blood 2005, 105, 4470-4476.
135. Pedranzini, L.; Dechow, T.; Berishaj, M.; Comenzo, R.; Zhou, P.; Azare, J.; Bornmann, W.; Bromberg, J. Pyridone 6, a pan-Janusactivated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res. 2006, 66, 9714-9721.
136. Pathak, A. K.; Bhutani, M.; Nair, A. S.; Ahn, K. S.; Chakraborty, A.; Kadara, H.; Guha, S.; Sethi, G.; Aggarwal, B. B. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol. Cancer Res. 2007, 5, 943-955.
137. Bhutani, M.; Pathak, A. K.; Nair, A. S.; Kunnumakkara, A. B.; Guha, S.; Sethi, G.; Aggarwal, B. B. Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin. Cancer Res. 2007, 13, 3024-3032.
138. Ahn, K. S.; Sethi, G.; Sung, B.; Goel, A.; Ralhan, R.; Aggarwal, B. B. Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1. Cancer Res. 2008, 68, 4406-4415.
139. Qiang, Y. W.; Endo, Y.; Rubin, J. S.; Rudikoff, S. Wnt signaling in B-cell neoplasia. Oncogene 2003, 22, 1536-1545.
140. Derksen, P. W.; Tjin, E.; Meijer, H. P.; Klok, M. D.; MacGillavry, H. D.; van Oers, M. H.; Lokhorst, H. M.; Bloem, A. C.; Clevers, H.; Nusse, R.; van der Neut, R.; Spaargaren, M.; Pals, S. T. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc. Natl. Acad. Sci. USA 2004, 101, 6122-6127.
141. Sukhdeo, K.; Mani, M.; Zhang, Y.; Dutta, J.; Yasui, H.; Rooney, M. D.; Carrasco, D. E.; Zheng, M.; He, H.; Tai, Y. T.; Mitsiades, C.; Anderson, K. C.; Carrasco, D. R. Targeting the betacatenin/ TCF transcriptional complex in the treatment of multiple myeloma. Proc. Natl. Acad. Sci. USA 2007, 104, 7516-7521.
142. Tian, E.; Zhan, F.; Walker, R.; Rasmussen, E.; Ma, Y.; Barlogie, B.; Shaughnessy, J. D. Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med. 2003, 349, 2483-2494.
143. Yaccoby, S.; Ling, W.; Zhan, F.; Walker, R.; Barlogie, B.; Shaughnessy, J. D. Jr. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007, 109, 2106-2111.
144. Fulciniti, M.; Tassone, P.; Hideshima, T.; Vallet, S.; Nanjappa, P.; Ettenberg, S. A.; Shen, Z.; Patel, N.; Tai, Y. T.; Chauhan, D.; Mitsiades, C.; Prabhala, R.; Raje, N.; Anderson, K. C.; Stover, D. R.; Munshi, N. C. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009, 114, 371-379.
145. Podar, K.; Raab, M. S.; Chauhan, D.; Anderson, K. C. The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin. Investig. Drugs 2007, 16, 1693-1707.
146. Mitsiades, C. S.; Mitsiades, N. S.; McMullan, C. J.; Poulaki, V.; Kung, A. L.; Davies, F. E.; Morgan, G.; Akiyama, M.; Shringarpure, R.; Munshi, N. C.; Richardson, P. G.; Hideshima, T.; Chauhan, D.; Gu, X.; Bailey, C.; Joseph, M.; Libermann, T. A.; Rosen, N. S. Anderson, K. C. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006, 107, 1092-1100.
147. 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, K. C. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood 2009, 113, 846-855.
148. Nakashima, T.; Ishii, T.; Tagaya, H.; Seike, T.; Nakagawa, H.; Kanda, Y.; Akinaga, S.; Soga, S.; Shiotsu, Y. New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin. Cancer Res. 2010, 16, 2792-2802.
149. Richardson, P. G.; Mitsiades, C. S.; Laubach, J. P.; Lonial, S.; Chanan-Khan, A. A.; Anderson, K. C. Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers. Br. J. Haematol. 2011, 152, 367-379.
150. Zhang, H.; Vakil, V.; Braunstein, M.; Smith, E. L.; Maroney, J.; Chen, L.; Dai, K.; Berenson, J. R.; Hussain, M. M.; Klueppelberg, U.; Norin, A. J.; Akman, H. O.; Ozcelik, T.; Batuman, O. A. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 2005, 105, 3286-3294.
151. de Bont, E. S.; Guikema, J. E.; Scherpen, F.; Meeuwsen, T.; Kamps, W. A.; Vellenga, E.; Bos, N. A. Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma. Cancer Res. 2001, 61, 7654-7659.
152. Scavelli, C.; Nico, B.; Cirulli, T.; Ria, R.; Di Pietro, G.; Mangieri, D.; Bacigalupo, A.; Mangialardi, G.; Coluccia, A. M.; Caravita, T.; Molica, S.; Ribatti, D.; Dammacco, F.; Vacca, A. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene 2008, 27, 663-674.
153. Vacca, A.; Ria, R.; Semeraro, F.; Merchionne, F.; Coluccia, M.; Boccarelli, A.; Scavelli, C.; Nico, B.; Gernone, A.; Battelli, F.; Tabilio, A.; Guidolin, D.; Petrucci, M. T.; Ribatti, D.; Dammacco, F. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood 2003, 102, 3340-3348.
154. Pellegrino, A.; Ria, R.; Pietro, G. D.; Cirulli, T.; Surico, G.; Pennisi, A.; Morabito, F.; Ribatti, D.; Vacca, A. Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells. Br. J. Haematol. 2005, 129, 248-256.
155. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nat. Rev. Drug Discov. 2007, 6, 273-286.
156. Podar, K.; Anderson, K. C. Inhibition of VEGF signaling pathways in multiple myeloma and other malignancies. Cell Cycle 2007, 6, 538-542.
157. O'Farrell, A. M.; Yuen, H. A.; Smolich, B.; Hannah, A. L.; Louie, S. G.; Hong, W.; Stopeck, A. T.; Silverman, L. R.; Lancet, J. E.; Karp, J. E.; Albitar, M.; Cherrington, J. M.; Giles, F. J. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk. Res. 2004, 28, 679-689.
158. Giles, F. J.; Stopeck, A. T.; Silverman, L. R.; Lancet, J. E.; Cooper, M. A.; Hannah, A. L.; Cherrington, J. M.; O'Farrell, A. M.; Yuen, H. A.; Louie, S. G.; Hong, W.; Cortes, J. E.; Verstovsek, S.; Albitar, M.; O'Brien, S. M.; Kantarjian, H. M.; Karp, J. E. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003, 102, 795-801.
159. Fiedler, W.; Mesters, R.; Tinnefeld, H.; Loges, S.; Staib, P.; Duhrsen, U.; Flasshove, M.; Ottmann, O. G.; Jung, W.; Cavalli, F.; Kuse, R.; Thomalla, J.; Serve, H.; O'Farrell, A. M.; Jacobs, M.; Brega, N. M.; Scigalla, P.; Hossfeld, D. K.; Berdel, W. E. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003, 102, 2763-2767.
160. O'Farrell, A. M.; Abrams, T. J.; Yuen, H. A.; Ngai, T. J.; Louie, S. G.; Yee, K. W.; Wong, L. M.; Hong, W.; Lee, L. B.; Town, A.; Smolich, B. D.; Manning, W. C.; Murray, L. J.; Heinrich, M. C.; Cherrington, J. M. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003, 101, 3597-3605.
161. Beebe, J. S.; Jani, J. P.; Knauth, E.; Goodwin, P.; Higdon, C.; Rossi, A. M.; Emerson, E.; Finkelstein, M.; Floyd, E.; Harriman, S.; Atherton, J.; Hillerman, S.; Soderstrom, C.; Kou, K.; Gant, T.; Noe, M. C.; Foster, B.; Rastinejad, F.; Marx, M. A.; Schaeffer, T.; Whalen, P. M.; Roberts, W. G. Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res. 2003, 63, 7301-7309.
162. Bates, D. ZD-6474. AstraZeneca. Curr. Opin. Investig. Drugs 2003, 4, 1468-1472.
163. Podar, K.; Tonon, G.; Sattler, M.; Tai, Y. T.; Legouill, S.; Yasui, H.; Ishitsuka, K.; Kumar, S.; Kumar, R.; Pandite, L. N.; Hideshima, T.; Chauhan, D.; Anderson, K. C. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc. Natl. Acad. Sci. USA 2006, 103, 19478-19483
164. Fan, F.; Schimming, A.; Jaeger, D.; Podar, K. Targeting the tumor microenvironment: focus on angiogenesis. J. Oncol. 2012, 2012, 281261.
165. Sezer, O.; Heider, U.; Zavrski, I.; Kuhne, C. A.; Hofbauer, L. C. RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003, 101, 2094-2098.
166. Yao, Z.; Xing, L.; Qin, C.; Schwarz, E. M.; Boyce, B. F. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism. J. Biol. Chem. 2008, 283, 9917-9924.
167. Liu, X. H.; Kirschenbaum, A.; Yao, S.; Levine, A. C. Cross-talk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-{kappa}B (RANK) ligand/RANK system. Endocrinology 2005, 146, 1991-1998.
168. Han, J. H.; Choi, S. J.; Kurihara, N.; Koide, M.; Oba, Y.; Roodman, G. D. Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 2001, 97, 3349-3353.
169. Giuliani, N.; Lisignoli, G.; Colla, S.; Lazzaretti, M.; Storti, P.; Mancini, C.; Bonomini, S.; Manferdini, C.; Codeluppi, K.; Facchini, A.; Rizzoli, V. CC-Chemokine ligand 20/macrophage inflammatory protein-3alpha and CC-chemokine receptor 6 are overexpressed in myeloma microenvironment related to osteolytic bone lesions. Cancer Res. 2008, 68, 6840-6850.
170. Giuliani, N.; Morandi, F.; Tagliaferri, S.; Lazzaretti, M.; Donofrio, G.; Bonomini, S.; Sala, R.; Mangoni, M.; Rizzoli, V. Production of Wnt inhibitors by myeloma cells: potential effects on canonical Wnt pathway in the bone microenvironment. Cancer Res. 2007, 67, 7665-7674.
171. Abe, M.; Hiura, K.; Wilde, J.; Shioyasono, A.; Moriyama, K.; Hashimoto, T.; Kido, S.; Oshima, T.; Shibata, H.; Ozaki, S.; Inoue, D.; Matsumoto, T. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 2004, 104, 2484-2491.
172. Yaccoby, S.; Wezeman, M. J.; Zangari, M.; Walker, R.; Cottler-Fox, M.; Gaddy, D.; Ling, W.; Saha, R.; Barlogie, B.; Tricot, G.; Epstein, J. Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica 2006, 91, 192-199.
173. Morgan, G. J.; Davies, F. E.; Gregory, W. M.; Cocks, K.; Bell, S. E.; Szubert, A. J.; Navarro-Coy, N.; Drayson, M. T.; Owen, R. G.; Feyler, S.; Ashcroft, A. J.; Ross, F.; Byrne, J.; Roddie, H.; Rudin, C.; Cook, G.; Jackson, G. H.; Child, J. A. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010, 376, 1989-1999.
174. Choi, S. J.; Oba, Y.; Gazitt, Y.; Alsina, M.; Cruz, J.; Anderson, J.; Roodman, G. D. Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J. Clin. Invest. 2001, 108, 1833-1841.
175. Edwards, C. M.; Mueller, G.; Roelofs, A. J.; Chantry, A.; Perry, M.; Russell, R. G.; Van Camp, B.; Guyon-Gellin, Y.; Niesor, E. J.; Bentzen, C. L.; Vanderkerken, K.; Croucher, P. I. Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo. Int. J. Cancer 2007, 120, 1657-1663.
176. Vallet, S.; Mukherjee, S.; Vaghela, N.; Hideshima, T.; Fulciniti, M.; Pozzi, S.; Santo, L.; Cirstea, D.; Patel, K.; Sohani, A. R.; Guimaraes, A.; Xie, W.; Chauhan, D.; Schoonmaker, J. A.; Attar, E.; Churchill, M.; Weller, E.; Munshi, N.; Seehra, J. S.; Weissleder, R.; Anderson, K. C.; Scadden, D. T.; 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, 5124-5129.
177. Chantry, A. D.; Heath, D.; Mulivor, A. W.; Pearsall, S.; Baud'huin, M.; Coulton, L.; Evans, H.; Abdul, N.; Werner, E. D.; Bouxsein, M. L.; Key, M. L.; Seehra, J.; Arnett, T. R.; Vanderkerken, K.; Croucher, P. Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. J. Bone Miner. Res. 2010, 25, 2633-2646.
178. Kerbel, R. S.; Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer 2004, 4, 423-436.
179. Podar, K.; Richardson, P. G.; Chauhan, D.; Anderson, K. C. Targeting the vascular endothelial growth factor pathway in the treatment of multiple myeloma. Expert Rev. Anticancer Ther. 2007, 7, 551-566.
180. Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.; Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.; Berkers, C.; Nicholson, B.; Chao, T. H.; Neuteboom, S. T.; Richardson, P.; Palladino, M. A.; Anderson, K. C. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005, 8, 407-419.
181. Kuhn, D. J.; Chen, Q.; Voorhees, P. M.; Strader, J. S.; Shenk, K. D.; Sun, C. M.; Demo, S. D.; Bennett, M. K.; van Leeuwen, F. W.; Chanan-Khan, A. A.; Orlowski, R. Z. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitinproteasome pathway, against preclinical models of multiple myeloma. Blood 2007, 110, 3281-3290.
182. Tai, Y. T.; Catley, L. P.; Mitsiades, C. S.; Burger, R.; Podar, K.; Shringpaure, R.; Hideshima, T.; Chauhan, D.; Hamasaki, M.; Ishitsuka, K.; Richardson, P.; Treon, S. P.; Munshi, N. C.; Anderson, K. C. Mechanisms by which SGN-40, a humanized anti- CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res. 2004, 64, 2846-2852.
183. Tai, Y. T.; Li, X. F.; Catley, L.; Coffey, R.; Breitkreutz, I.; Bae, J.; Song, W.; Podar, K.; Hideshima, T.; Chauhan, D.; Schlossman, R.; Richardson, P.; Treon, S. P.; Grewal, I. S.; Munshi, N. C.; Anderson, K. C. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005, 65, 11712-11720.
184. Moreau, P.; Cavallo, F.; Leleu, X.; Hulin, C.; Amiot, M.; Descamps, G.; Facon, T.; Boccadoro, M.; Mignard, D.; Harousseau, J. L. Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. Leuk. 2011, 25, 872-874.