Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy

Abstract

Thalidomide and its analogues (lenalidomide and pomalidomide) are small molecule glutamic acid derivatives of the immunomodulatory drug (IMiD) class. In addition to the immuno-adjuvant and anti-inflammatory properties that define an IMiD, the thalidomide analogues demonstrate an overlapping and diverse range of biological activities, including anti-angiogenic, teratogenic and epigenetic effects. Importantly, the IMiDs possess anti-cancer activity with selectivity for molecularly defined subgroups of hematological malignancies, specifically mature B-cell neoplasms and myelodysplasia with deletion of chromosome 5q. Emerging insight into the pathophysiological drivers of these IMiD-responsive disease states can now be synthesized using previously disclosed IMiD activities and recently discovered thalidomide targets to build unifying models of IMiD mechanism of action. Attention to mechanisms of IMiD-induced clinical toxicities, in particular the recently identified association of lenalidomide with second primary malignancies, provides an additional tool for determination of drug mechanism. This review seeks to define the molecular IMiD targets and biological outputs that underpin their anti-neoplastic activity. It is anticipated that elucidation of important IMiD targets will allow the rational development of new-generation therapeutics with the potential to separate thalidomide-analogue efficacy from clinical toxicity.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Mellin GW, Katzenstein M . The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med 1962; 267: 1184–1192.

    CAS  Google Scholar 

  2. McBride WG . Thalidomide and congenital abnormalities. Lancet 1961; 278: 1358.

    Google Scholar 

  3. Lenz W, Pfeiffer RA, Kosenow W, Hayman DJ . Thalidomide and congenital abnormalities. Lancet 1962; 279: 45–46.

    Google Scholar 

  4. Iyer CG, Languillon J, Ramanujam K, Tarabini-Castellani G, De las Aguas JT, Bechelli LM et al. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ 1971; 45: 719–732.

    CAS  Google Scholar 

  5. Sheskin J . Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther 1965; 6: 303–306.

    CAS  Google Scholar 

  6. Wohl DA, Aweeka FT, Schmitz J, Pomerantz R, Cherng DW, Spritzler J et al. Safety, tolerability, and pharmacokinetic effects of thalidomide in patients infected with human immunodeficiency virus: AIDS Clinical Trials Group 267. J Infect Dis 2002; 185: 1359–1363.

    CAS  Google Scholar 

  7. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med 1997; 336: 1487–1493.

    CAS  Google Scholar 

  8. Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128: 443–450.

    CAS  Google Scholar 

  9. Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB . Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999; 117: 1271–1277.

    CAS  Google Scholar 

  10. Cortes-Hernandez J, Torres-Salido M, Castro-Marrero J, Vilardell-Tarres M, Ordi-Ros J . Thalidomide in the treatment of refractory cutaneous lupus erythematosus: prognostic factors of clinical outcome. Br J Dermatol 2012; 166: 616–623.

    CAS  Google Scholar 

  11. Bartlett JB, Dredge K, Dalgleish AG . The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4: 314–322.

    CAS  Google Scholar 

  12. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163: 380–386.

    CAS  Google Scholar 

  13. Kenyon BM, Browne F, D’Amato RJ . Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997; 64: 971–978.

    CAS  Google Scholar 

  14. Eriksson T, Bjorkman S, Roth B, Fyge A, Hoglund P . Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 1995; 7: 44–52.

    CAS  Google Scholar 

  15. Lepper ER, Smith NF, Cox MC, Scripture CD, Figg WD . Thalidomide metabolism and hydrolysis: mechanisms and implications. Curr Drug Metab. 2006; 7: 677–685.

    CAS  Google Scholar 

  16. Muller GW, Corral LG, Shire MG, Wang H, Moreira A, Kaplan G et al. Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J Med Chem 1996; 39: 3238–3240.

    CAS  Google Scholar 

  17. Muller GW, Chen R, Huang SY, Corral LG, Wong LM, Patterson RT et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999; 9: 1625–1630.

    CAS  Google Scholar 

  18. Barnes PF, Chatterjee D, Brennan PJ, Rea TH, Modlin RL . Tumor necrosis factor production in patients with leprosy. Infect Immun 1992; 60: 1441–1446.

    CAS  Google Scholar 

  19. Tsimberidou AM, Waddelow T, Kantarjian HM, Albitar M, Giles FJ . Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment. Leuk Res 2003; 27: 375–380.

    CAS  Google Scholar 

  20. Madan S, Lacy MQ, Dispenzieri A, Gertz MA, Buadi F, Hayman SR et al. Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. Blood 2011; 118: 1763–1765.

    CAS  Google Scholar 

  21. Tsenova L, Mangaliso B, Muller G, Chen Y, Freedman VH, Stirling D et al. Use of IMiD3, a thalidomide analog, as an adjunct to therapy for experimental tuberculous meningitis. Antimicrob Agents Chemother 2002; 46: 1887–1895.

    CAS  Google Scholar 

  22. Giamarellos-Bourboulis EJ, Poulaki H, Kostomitsopoulos N, Dontas I, Perrea D, Karayannacos PE et al. Effective immunomodulatory treatment of Escherichia coli experimental sepsis with thalidomide. Antimicrob Agents Chemother 2003; 47: 2445–2449.

    CAS  Google Scholar 

  23. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G . Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173: 699–703.

    CAS  Google Scholar 

  24. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G . Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993; 177: 1675–1680.

    CAS  Google Scholar 

  25. Li S, Pal R, Monaghan SA, Schafer P, Ouyang H, Mapara M et al. IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E downregulation resulting in inhibition of MM. Blood 2011; 117: 5157–5165.

    CAS  Google Scholar 

  26. Ferguson GD, Jensen-Pergakes K, Wilkey C, Jhaveri U, Richard N, Verhelle D et al. Immunomodulatory drug CC-4047 is a cell-type and stimulus-selective transcriptional inhibitor of cyclooxygenase 2. J Clin Immunol 2007; 27: 210–220.

    CAS  Google Scholar 

  27. Welm AL, Mackey SL, Timchenko LT, Darlington GJ, Timchenko NA. . Translational induction of liver-enriched transcriptional inhibitory protein during acute phase response leads to repression of CCAAT/enhancer binding protein alpha mRNA. J Biol Chem 2000; 275: 27406–27413.

    CAS  Google Scholar 

  28. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–1311.

    CAS  Google Scholar 

  29. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946–1952.

    CAS  Google Scholar 

  30. Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A et al. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol 2011; 29: 4320–4326.

    CAS  Google Scholar 

  31. Hoang B, Zhu L, Shi Y, Frost P, Yan H, Sharma S et al. Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance. Blood 2006; 107: 4484–4490.

    CAS  Google Scholar 

  32. Prince HM, Mileshkin L, Roberts A, Ganju V, Underhill C, Catalano J et al. A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma. Clin Cancer Res 2005; 11: 5504–5514.

    CAS  Google Scholar 

  33. Dredge K, Marriott JB, Todryk SM, Muller GW, Chen R, Stirling DI et al. Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity. J Immunol 2002; 168: 4914–4919.

    CAS  Google Scholar 

  34. Noonan K, Rudraraju L, Ferguson A, Emerling A, Pasetti MF, Huff CA et al. Lenalidomide-induced immunomodulation in multiple myeloma: impact on vaccines and antitumor responses. Clin Cancer Res 2012; 18: 1426–1434.

    CAS  Google Scholar 

  35. Haslett PA, Corral LG, Albert M, Kaplan G . Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 1998; 187: 1885–1892.

    CAS  Google Scholar 

  36. LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood 2004; 103: 1787–1790.

    CAS  Google Scholar 

  37. Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 2005; 128: 192–203.

    CAS  Google Scholar 

  38. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98: 210–216.

    CAS  Google Scholar 

  39. Payvandi F, Wu L, Naziruddin SD, Haley M, Parton A, Schafer PH et al. Immunomodulatory drugs (IMiDs) increase the production of IL-2 from stimulated T cells by increasing PKC-theta activation and enhancing the DNA-binding activity of AP-1 but not NF-kappaB, OCT-1, or NF-AT. J Interferon Cytokine Res 2005; 25: 604–616.

    CAS  Google Scholar 

  40. Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA et al. The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood 2011; 117: 1605–1613.

    CAS  Google Scholar 

  41. Gandhi AK, Kang J, Capone L, Parton A, Wu L, Zhang LH et al. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets 2010; 10: 155–167.

    CAS  Google Scholar 

  42. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS . Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 2005; 11: 5984–5992.

    CAS  Google Scholar 

  43. D'Amato RJ, Loughnan MS, Flynn E, Folkman J . Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91: 4082–4085.

    CAS  Google Scholar 

  44. Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y et al. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 2005; 69: 56–63.

    CAS  Google Scholar 

  45. Bauer KS, Dixon SC, Figg WD . Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 1998; 55: 1827–1834.

    CAS  Google Scholar 

  46. Yaccoby S, Johnson CL, Mahaffey SC, Wezeman MJ, Barlogie B, Epstein J . Antimyeloma efficacy of thalidomide in the SCID-hu model. Blood 2002; 100: 4162–4168.

    CAS  Google Scholar 

  47. Lu L, Payvandi F, Wu L, Zhang LH, Hariri RJ, Man HW et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 2009; 77: 78–86.

    CAS  Google Scholar 

  48. Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001; 15: 1950–1961.

    CAS  Google Scholar 

  49. Yabu T, Tomimoto H, Taguchi Y, Yamaoka S, Igarashi Y, Okazaki T . Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate. Blood 2005; 106: 125–134.

    CAS  Google Scholar 

  50. Ito T, Ando H, Handa H . Teratogenic effects of thalidomide: molecular mechanisms. Cell Mol Life Sci 2011; 68: 1569–1579.

    CAS  Google Scholar 

  51. Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N . Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc Natl Acad Sci USA 2009; 106: 8573–8578.

    CAS  Google Scholar 

  52. Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002; 87: 1166–1172.

    CAS  Google Scholar 

  53. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327: 1345–1350.

    CAS  Google Scholar 

  54. Knobloch J, Shaughnessy JD, Ruther U . Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway. Faseb J 2007; 21: 1410–1421.

    CAS  Google Scholar 

  55. Knobloch J, Schmitz I, Gotz K, Schulze-Osthoff K, Ruther U . Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspase-dependent cell death. Mol Cell Biol 2008; 28: 529–538.

    CAS  Google Scholar 

  56. Stephens TD, Bunde CJ, Fillmore BJ . Mechanism of action in thalidomide teratogenesis. Biochem Pharmacol 2000; 59: 1489–1499.

    CAS  Google Scholar 

  57. Parman T, Wiley MJ, Wells PG . Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 1999; 5: 582–585.

    CAS  Google Scholar 

  58. Hansen JM, Gong SG, Philbert M, Harris C . Misregulation of gene expression in the redox-sensitive NF-kappab-dependent limb outgrowth pathway by thalidomide. Dev Dyn 2002; 225: 186–194.

    CAS  Google Scholar 

  59. Xin W, Xiaohua N, Peilin C, Xin C, Yaqiong S, Qihan W . Primary function analysis of human mental retardation gene CRBN. Mol Biol Rep 2008; 35: 251–256.

    Google Scholar 

  60. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP . A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 2004; 63: 1927–1931.

    CAS  Google Scholar 

  61. Hohberger B, Enz R . Cereblon is expressed in the retina and binds to voltage-gated chloride channels. FEBS Lett 2009; 583: 633–637.

    CAS  Google Scholar 

  62. Jo S, Lee KH, Song S, Jung YK, Park CS . Identification and functional characterization of cereblon as a binding protein for large-conductance calcium-activated potassium channel in rat brain. J Neurochem 2005; 94: 1212–1224.

    CAS  Google Scholar 

  63. Lee KM, Jo S, Kim H, Lee J, Park CS . Functional modulation of AMP-activated protein kinase by cereblon. Biochem Biophys Acta 2011; 1813: 448–455.

    CAS  Google Scholar 

  64. Figg WD, Raje S, Bauer KS, Tompkins A, Venzon D, Bergan R et al. Pharmacokinetics of thalidomide in elderly prostate cancer population. J Pharm Sci 1999; 88: 121–125.

    CAS  Google Scholar 

  65. Cheng J, Gu YJ, Wang Y, Cheng SH, Wong WT . Nanotherapeutics in angiogenesis: synthesis and in vivo assessment of drug efficacy and biocompatibility in zebrafish embryos. Int J Nanomedicine 2011; 6: 2007–2021.

    CAS  Google Scholar 

  66. Ashby J, Tinwell H, Callander RD, Kimber I, Clay P, Galloway SM et al. Thalidomide: lack of mutagenic activity across phyla and genetic endpoints. Mutat Res 1997; 396: 45–64.

    CAS  Google Scholar 

  67. Huang PH, McBride WG . Interaction of [glutarimide-2-14C]-thalidomide with rat embryonic DNA in vivo. Teratog Carcinog Mutagen 1997; 17: 1–5.

    CAS  Google Scholar 

  68. Jonsson NA . Chemical structure and teratogenic properties. IV. An outline of a chemical hypothesis for the teratogenic action of thalidomide. Acta Pharm Suec 1972; 9: 543–562.

    CAS  Google Scholar 

  69. Jackson SP, MacDonald JJ, Lees-Miller S, Tjian R . GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell 1990; 63: 155–165.

    CAS  Google Scholar 

  70. Narayan VA, Kriwacki RW, Caradonna JP . Structures of zinc finger domains from transcription factor Sp1. Insights into sequence-specific protein-DNA recognition. J Biol Chem 1997; 272: 7801–7809.

    CAS  Google Scholar 

  71. Gandhi AK, Kang J, Naziruddin S, Parton A, Schafer PH, Stirling DI . Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly. Leuk Res 2006; 30: 849–858.

    CAS  Google Scholar 

  72. Escoubet-Lozach L, Lin I-L, Jensen-Pergakes K, Brady HA, Gandhi AK, Schafer PH et al. Pomalidomide and lenalidomide induce p21WAF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism. Cancer Res 2009; 69: 7347–7356.

    CAS  Google Scholar 

  73. Gorgun G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010; 116: 3227–3237.

    CAS  Google Scholar 

  74. Croker BA, Kiu H, Nicholson SE . SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 2008; 19: 414–422.

    CAS  Google Scholar 

  75. Depil S, Saudemont A, Quesnel B . SOCS-1 gene methylation is frequent but does not appear to have prognostic value in patients with multiple myeloma. Leukemia 2003; 17: 1678–1679.

    CAS  Google Scholar 

  76. Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G . Distinct haematological disorder with deletion of long arm of no. 5 chromosome. Nature 1974; 251: 437–438.

    CAS  Google Scholar 

  77. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355: 1456–1465.

    CAS  Google Scholar 

  78. Boultwood J, Fidler C, Strickson AJ, Watkins F, Gama S, Kearney L et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood 2002; 99: 4638–4641.

    CAS  Google Scholar 

  79. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451: 335–339.

    CAS  Google Scholar 

  80. Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 1999; 21: 169–175.

    CAS  Google Scholar 

  81. Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet 2006; 79: 1110–1118.

    CAS  Google Scholar 

  82. Barlow JL, Drynan LF, Hewett DR, Holmes LR, Lorenzo-Abalde S, Lane AL et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med 2010; 16: 59–66.

    CAS  Google Scholar 

  83. Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, Megerdichian C et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 2011; 117: 2567–2576.

    CAS  Google Scholar 

  84. Kumar MS, Narla A, Nonami A, Mullally A, Dimitrova N, Ball B et al. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood 2011; 118: 4666–4673.

    CAS  Google Scholar 

  85. Pellagatti A, Jadersten M, Forsblom A-M, Cattan H, Christensson B, Emanuelsson EK et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci USA 2007; 104: 11406–11411.

    CAS  Google Scholar 

  86. Wei S, Chen X, Rocha K, Epling-Burnette PK, Djeu JY, Liu Q et al. A critical role for phosphatase deficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci USA 2009; 106: 12974–12979.

    CAS  Google Scholar 

  87. Jadersten M, Saft L, Pellagatti A, Gohring G, Wainscoat JS, Boultwood J et al. Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica 2009; 91: 1762–1766.

    Google Scholar 

  88. Wei S, Chen X, McGraw K, Zhang L, Komrokji R, Clark J et al. Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene 2013; 32: 1110–1120.

    CAS  Google Scholar 

  89. Palumbo A, Freeman J, Weiss L, Fenaux P . The clinical safety of lenalidomide in multiple myeloma and myelodysplastic syndromes. Expert Opin Drug Saf 2012; 11: 107–120.

    CAS  Google Scholar 

  90. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012; 366: 1759–1769.

    CAS  Google Scholar 

  91. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1782–1791.

    CAS  Google Scholar 

  92. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1770–1781.

    CAS  Google Scholar 

  93. Kyle RA, Rajkumar SV . Multiple myeloma. Blood 2008; 111: 2962–2972.

    CAS  Google Scholar 

  94. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011; 471: 467–472.

    CAS  Google Scholar 

  95. Yang Y, Shaffer AL, Emre NC, Ceribelli M, Zhang M, Wright G et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 2012; 21: 723–737.

    CAS  Google Scholar 

  96. Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W et al. IRF4 addiction in multiple myeloma. Nature 2008; 454: 226–231.

    CAS  Google Scholar 

  97. Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470: 115–119.

    CAS  Google Scholar 

  98. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99: 4525–4530.

    CAS  Google Scholar 

  99. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012; 26: 2326–2335.

    CAS  Google Scholar 

  100. Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011; 118: 4771–4779.

    CAS  Google Scholar 

  101. Nefedova Y, Landowski TH, Dalton WS . Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 2003; 17: 1175–1182.

    CAS  Google Scholar 

  102. Mitsiades CS, Mitsiades NS, Richardson PG, Munshi NC, Anderson KC . Multiple myeloma: a prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment. J Cell Biochem 2007; 101: 950–968.

    CAS  Google Scholar 

  103. Cheung WC, Van Ness B . The bone marrow stromal microenvironment influences myeloma therapeutic response in vitro. Leukemia 2001; 15: 264–271.

    CAS  Google Scholar 

  104. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93: 1658–1667.

    CAS  Google Scholar 

  105. McMillin DW, Delmore J, Weisberg E, Negri JM, Geer DC, Klippel S et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med 2010; 16: 483–489.

    CAS  Google Scholar 

  106. Shi Y, Frost P, Hoang B, Benavides A, Gera J, Lichtenstein A . IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the RNA-binding protein hnRNP A1. J Biol Chem 2011; 286: 67–78.

    CAS  Google Scholar 

  107. Landowski TH, Megli CJ, Nullmeyer KD, Lynch RM, Dorr RT . Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer Res 2005; 65: 3828–3836.

    CAS  Google Scholar 

  108. Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 2002; 21: 5673–5683.

    CAS  Google Scholar 

  109. Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y-T et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943–2950.

    CAS  Google Scholar 

  110. Jakubikova J, Adamia S, Kost-Alimova M, Klippel S, Cervi D, Daley JF et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood 2011; 117: 4409–4419.

    CAS  Google Scholar 

  111. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008; 68: 190–197.

    CAS  Google Scholar 

  112. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 4048–4053.

    CAS  Google Scholar 

  113. Pilarski LM, Belch AR . Clonotypic myeloma cells able to xenograft myeloma to nonobese diabetic severe combined immunodeficient mice copurify with CD34 (+) hematopoietic progenitors. Clin Cancer Res 2002; 8: 3198–3204.

    Google Scholar 

  114. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797–1806.

    CAS  Google Scholar 

  115. Bernal M, Garrido P, Jimenez P, Carretero R, Almagro M, Lopez P et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: implications for tumor evasion of T and NK cells. Hum Immunol 2009; 70: 854–857.

    CAS  Google Scholar 

  116. Jinushi M, Vanneman M, Munshi NC, Tai YT, Prabhala RH, Ritz J et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA 2008; 105: 1285–1290.

    CAS  Google Scholar 

  117. Racanelli V, Leone P, Frassanito MA, Brunetti C, Perosa F, Ferrone S et al. Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma. Blood 2010; 115: 1185–1193.

    CAS  Google Scholar 

  118. El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res 2007; 67: 8444–8449.

    CAS  Google Scholar 

  119. Dauguet N, Fournie JJ, Poupot R, Poupot M . Lenalidomide down regulates the production of interferon-gamma and the expression of inhibitory cytotoxic receptors of human Natural Killer cells. Cell Immunol 2010; 264: 163–170.

    CAS  Google Scholar 

  120. Tai Y-T, Li X-F, Catley L, Coffey R, Breitkreutz I, Bae J et al. 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.

    CAS  Google Scholar 

  121. Tai YT, Horton HM, Kong SY, Pong E, Chen H, Cemerski S et al. Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function. Blood 2012; 119: 2074–2082.

    CAS  Google Scholar 

  122. Benson DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel, monoclonal anti-PD-1 antibody. Blood 2010; 116: 2286–2294.

    CAS  Google Scholar 

  123. Lanier LL . Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008; 9: 495–502.

    CAS  Google Scholar 

  124. Bernal M, Garrido P, Jiménez P, Carretero R, Almagro M, López P et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: implications for tumor evasion of T and NK cells. Hum Immunol 2009; 70: 854–857.

    CAS  Google Scholar 

  125. Benson DM, Bakan CE, Zhang S, Collins SM, Liang J, Srivastava S et al. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood 2011; 118: 6387–6391.

    CAS  Google Scholar 

  126. Cook G, Campbell JD, Carr CE, Boyd KS, Franklin IM . Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol 1999; 66: 981–988.

    CAS  Google Scholar 

  127. Frassanito MA, Cusmai A, Dammacco F . Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin Exp Immunol 2001; 125: 190–197.

    CAS  Google Scholar 

  128. Sze DM, Giesajtis G, Brown RD, Raitakari M, Gibson J, Ho J et al. Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8(+)CD57(+)CD28(−) compartment. Blood 2001; 98: 2817–2827.

    CAS  Google Scholar 

  129. Raitakari M, Brown RD, Sze D, Yuen E, Barrow L, Nelson M et al. T-cell expansions in patients with multiple myeloma have a phenotype of cytotoxic T cells. Br J Haematol 2000; 110: 203–209.

    CAS  Google Scholar 

  130. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, Schnetkamp PPM et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther 2003; 305: 1222–1232.

    CAS  Google Scholar 

  131. Luptakova K, Rosenblatt J, Glotzbecker B, Mills H, Stroopinsky D, Kufe T et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother (e-pub ahead of print 24 June 2012).

  132. Haslett PA, Hanekom WA, Muller G, Kaplan G . Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis 2003; 187: 946–955.

    CAS  Google Scholar 

  133. Giannopoulos K, Kaminska W, Hus I, Dmoszynska A . The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterisation of immune status in multiple myeloma. Br J Cancer 2012; 106: 546–552.

    CAS  Google Scholar 

  134. Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I . A novel role of IL-17 producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood 2010; 116: 3554–3563.

    CAS  Google Scholar 

  135. Galustian C, Meyer B, Labarthe M-C, Dredge K, Klaschka D, Henry J et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 2009; 58: 1033–1045.

    CAS  Google Scholar 

  136. Mileshkin L, Stark R, Day B, Seymour JF, Zeldis JB, Prince HM . Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol 2006; 24: 4507–4514.

    CAS  Google Scholar 

  137. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 2009; 27: 5008–5014.

    CAS  Google Scholar 

  138. Chaudhry V, Cornblath DR, Polydefkis M, Ferguson A, Borrello I . Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy. J Peripher Nerv Syst 2008; 13: 275–282.

    CAS  Google Scholar 

  139. Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 2011; 17: 2734–2743.

    CAS  Google Scholar 

  140. Cibeira MT, de Larrea CF, Navarro A, Diaz T, Fuster D, Tovar N et al. Impact on response and survival of DNA repair single nucleotide polymorphisms in relapsed or refractory multiple myeloma patients treated with thalidomide. Leuk Res 2011; 35: 1178–1183.

    CAS  Google Scholar 

  141. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Gastineau DA et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 2007; 21: 2035–2042.

    CAS  Google Scholar 

  142. Verhelle D, Corral LG, Wong K, Mueller JH, Moutouh-de Parseval L, Jensen-Pergakes K et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 67: 746–755.

    CAS  Google Scholar 

  143. Pal R, Monaghan SA, Hassett AC, Mapara MY, Schafer P, Roodman GD et al. Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood 2010; 115: 605–614.

    CAS  Google Scholar 

  144. Hirata RK, Chen ST, Weil SC . Expression of granule protein mRNAs in acute promyelocytic leukemia. Hematol Pathol 1993; 7: 225–238.

    CAS  Google Scholar 

  145. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109: 2068–2073.

    CAS  Google Scholar 

  146. Johnson DC, Corthals S, Ramos C, Hoering A, Cocks K, Dickens NJ et al. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping. Blood 2008; 112: 4924–4934.

    CAS  Google Scholar 

  147. Wittschieben BO, Iwai S, Wood RD . DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA. J Biol Chem 2005; 280: 39982–39989.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R W Johnstone.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shortt, J., Hsu, A. & Johnstone, R. Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy. Oncogene 32, 4191–4202 (2013). https://doi.org/10.1038/onc.2012.599

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.599

Keywords

  • immune modulation
  • therapeutics
  • hematological malignancies

This article is cited by

Search

Quick links