Cancer Immunology, Immunotherapy

, Volume 56, Issue 3, pp 343–357 | Cite as

Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis

  • Kai-Da Wu
  • Li Zhou
  • Douglas Burtrum
  • Dale L. Ludwig
  • Malcolm A. S. Moore
Original Article


Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum -induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.


Multiple myeloma Receptor tyrosine kinase IGF-IR Human antibody Anti-angiogenesis Targeted therapy 


  1. 1.
    Kyle RA, Rajkumar SV (2004) Multiple myeloma. N Engl J Med 351:1860PubMedCrossRefGoogle Scholar
  2. 2.
    Mitsiades CS, Mitsiades N, Munshi NC, Anderson KC (2004) Focus on multiple myeloma. Cancer Cell 6:439PubMedCrossRefGoogle Scholar
  3. 3.
    Barlogie B, Shaughnessy J, Tricot G, Jacobson J, Zangari M, Anaissie E, Walker R, Crowley J (2004) Treatment of multiple myeloma. Blood 103:20PubMedCrossRefGoogle Scholar
  4. 4.
    Fassas A, Shaughnessy J, Barlogie B (2005) Cure of myeloma: hype or reality? Bone Marrow Transplant 35:215PubMedCrossRefGoogle Scholar
  5. 5.
    Hideshima T, Chauhan D, Ishitsuka K, Yasui H, Raje N, Kumar S, Podar K, Mitsiades C, Hideshima H, Bonham L, Munshi NC, Richardson PG, Singer JW, Anderson KC (2005) Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. Oncogene 24:3121PubMedCrossRefGoogle Scholar
  6. 6.
    Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505PubMedCrossRefGoogle Scholar
  7. 7.
    Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB (2002) Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 95:2086PubMedCrossRefGoogle Scholar
  8. 8.
    Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM (2002) Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 62:2942PubMedGoogle Scholar
  9. 9.
    Happerfield LC, Miles DW, Barnes DM, Thomsen LL, Smith P, Hanby A (1997) The localization of the insulin-like growth factor receptor I (IGFR-I) in benign and malignant breast tissue. J Pathol 183:412PubMedCrossRefGoogle Scholar
  10. 10.
    Muller M, Dietel M, Turzynski A, Wiechen K (1998) Antisense phosphorothioate oligodeoxynucleotide down-regulation of the insulin-like growth factor I receptor in ovarian cancer cells. Int J Cancer 77:567PubMedCrossRefGoogle Scholar
  11. 11.
    Bergmann U, Funatomi H, Yokoyama M, Beger HG, Korc M (1995) Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res 55:2007PubMedGoogle Scholar
  12. 12.
    Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME, Rosen N (1990) Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50:48PubMedGoogle Scholar
  13. 13.
    Ankrapp DP, Bevan DR (1993) Insulin-like growth factor-I and human lung fibroblast-derived insulin-like growth factor I stimulate the proliferation of human lung carcinoma cells in vitro. Cancer Res 53:3399PubMedGoogle Scholar
  14. 14.
    Guo YS, Jin GF, Townsend CM Jr, Zhang T, Sheng HM, Beauchamp RD, Thompson JC (1995) Insulin-like growth factor II expression in carcinoma in colon cell lines: implications for autocrine actions. J Am Coll Surg 181:145PubMedGoogle Scholar
  15. 15.
    Kappel CC, Velez-Yanguas MC, Hirschfeld S, Helman LJ (1994) Human osteosarcoma cell lines are dependent on insulin-like growth factor I for in vitro growth. Cancer Res 54:2803PubMedGoogle Scholar
  16. 16.
    Steller MA, Delgado CH, Bartels CJ, Woodworth CD, Zou Z (1996) Overexpression of the insulin-like growth factor I receptor and autocrine stimulation in human cervical cancer cells. Cancer Res 56:1761PubMedGoogle Scholar
  17. 17.
    Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M (1998) Plasma insulin-like growth factor I and prostate cancer risk: a prospective study. Science 279:563PubMedCrossRefGoogle Scholar
  18. 18.
    Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ (1999) Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91:620PubMedCrossRefGoogle Scholar
  19. 19.
    Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X (1999) Plasma levels of insulin-like growth factor I and lung cancer risk: a case–control analysis. J Natl Cancer Inst 91:151PubMedCrossRefGoogle Scholar
  20. 20.
    Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M (1998) Circulating concentrations of insulin-like growth factor I and risk of breast cancer. Lancet 351:1393PubMedCrossRefGoogle Scholar
  21. 21.
    Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B (1997) The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332:F105PubMedGoogle Scholar
  22. 22.
    Navarro M, Baserga R (2001) Limited redundancy of survival signals from the type 1 insulin-like growth factor receptor. Endocrinology 142:1073PubMedCrossRefGoogle Scholar
  23. 23.
    Freund GG, Kulas DT, Way BA, Mooney RA (1994) Functional insulin and insulin-like growth factor-1 receptors are preferentially expressed in multiple myeloma cell lines as compared to B-lymphoblastoid cell lines. Cancer Res 54:3179PubMedGoogle Scholar
  24. 24.
    Ge NL, Rudikoff S (2000) Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood 96:2856PubMedGoogle Scholar
  25. 25.
    Carroll M, Abrams CS (2004) Signaling, drugs and apoptosis of myeloma cells. Cancer Biol Ther 3:195PubMedGoogle Scholar
  26. 26.
    Abroun S, Ishikawa H, Tsuyama N, Liu S, Li FJ, Otsuyama K, Zheng X, Obata M, Kawano MM (2004) Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I that highly express IL-6 receptor alpha myeloma cells. Blood 103:2291PubMedCrossRefGoogle Scholar
  27. 27.
    Tucci A, Bonadonna S, Cattaneo C, Ungari M, Giustina A, Guiseppe R (2003) Transformation of a MGUS to overt multiple myeloma: the possible role of a pituitary macroadenoma secreting high levels of insulin-like growth factor 1 (IGF-1). Leuk Lymphoma 44:543PubMedCrossRefGoogle Scholar
  28. 28.
    Qiang YW, Kopantzev E, Rudikoff S (2002) Insulin like growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. Blood 99:4138PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang X, Yee D (2000) Tyrosine kinase signalling in breast cancer: insulin-like growth factors and their receptors in breast cancer. Breast Cancer Res 2:170PubMedCrossRefGoogle Scholar
  30. 30.
    Tai YT, Podar K, Catley L, Tseng YH, Akiyama M, Shringarpure R, Burger R, Hideshima T, Chauhan D, Mitsiades N, Richardson P, Munshi NC, Kahn CR, Mitsiades C, Anderson KC (2003) Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3′-kinase/AKT signaling. Cancer Res 63:5850PubMedGoogle Scholar
  31. 31.
    Qiang YW, Yao L, Tosato G, Rudikoff S (2004) Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells. Blood 103:301PubMedCrossRefGoogle Scholar
  32. 32.
    Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H, Jimenez X, Johnson D, Apblett R, Kussie P, Bohlen P, Witte L, Hicklin DJ, Ludwig DL (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63:8912PubMedGoogle Scholar
  33. 33.
    Wu JD, Odman A, Higgins LM, Haugk K, Vessella R, Ludwig DL, Plymate SR (2005) In vivo effects of the human type 1 insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res 11:3065PubMedCrossRefGoogle Scholar
  34. 34.
    Vanderkerken K, Asosingh K, Braet F, Van Riet I, Van Camp B (1999) Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells. Blood 93:235PubMedGoogle Scholar
  35. 35.
    Gross JM, Yee D (2003) The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance. Cancer Metastasis Rev 22:327PubMedCrossRefGoogle Scholar
  36. 36.
    Qiang YW, Yao L, Tosato G, Rudikoff S (2004) Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells. Blood 103:301PubMedCrossRefGoogle Scholar
  37. 37.
    Ye JJ, Liang SJ, Guo N, Li SL, Wu AM, Giannini S, Sachdev D, Yee D, Brunner N, Ikle D, Fujita-Yamaguchi Y (2003) Combined effects of tamoxifen and a chimeric humanized single chain antibody against the type I IGF receptor on breast tumor growth in vivo. Horm Metab Res 35:836PubMedCrossRefGoogle Scholar
  38. 38.
    Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringapure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC, Kung AL (2004) 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 5:221PubMedCrossRefGoogle Scholar
  39. 39.
    Li W, Hyun T, Heller M, Yam A, Flechner L, Pierce JH, Rudikoff S (2000) Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth. Cancer Res 60:3909PubMedGoogle Scholar
  40. 40.
    Hilbert DM, Pumphrey JG, Troppmair J, Rapp UR, Rudikoff S (1993) Susceptibility and resistance to J3V1 retrovirus-induced murine plasmacytomagenesis in reconstituted severe combined immunodeficient mice. Oncogene 8:1993PubMedGoogle Scholar
  41. 41.
    Reinmuth N, Liu W, Fan F, Jung YD, Ahmad SA, Stoeltzing O, Bucana CD, Radinsky R, Ellis LM (2002) Blockade of insulin-like growth factor I receptor function inhibits growth and angiogenesis of colon cancer. Clin Cancer Res 8:3259PubMedGoogle Scholar
  42. 42.
    Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3PubMedCrossRefGoogle Scholar
  43. 43.
    Hakam A, Yeatman TJ, Lu L, Mora L, Marcet G, Nicosia SV, Karl RC, Coppola D (1999) Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 30:1128PubMedCrossRefGoogle Scholar
  44. 44.
    Menu E, Kooijman R, Van Valckenborgh E, Asosingh K, Bakkus M, Van Camp B, Vanderkerken K (2004) Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model. Br J Cancer 90:1076PubMedCrossRefGoogle Scholar
  45. 45.
    Ribas C, Colleoni GW, Silva MR, Carregoza MJ, Bordin JO (2004) Prognostic significance of vascular endothelial growth factor immunoexpression in the context of adverse standard prognostic factors in multiple myeloma. Eur J Haematol 73:311PubMedCrossRefGoogle Scholar
  46. 46.
    Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J, Shaughnessy J, Ayers D, Spoon D, Tricot G (2001) Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 98:492PubMedCrossRefGoogle Scholar
  47. 47.
    Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841PubMedGoogle Scholar
  48. 48.
    Rafii S, Lyden D (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9:702PubMedCrossRefGoogle Scholar
  49. 49.
    Ria R, Roccaro AM, Merchionne F, Vacca A, Dammacco F, Ribatti D (2003) Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia 17:1961PubMedCrossRefGoogle Scholar
  50. 50.
    Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Richardson P, Anderson KC (2001) Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 98:428PubMedCrossRefGoogle Scholar
  51. 51.
    Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, Greipp PR, Rajkumar SV (2003) Expression of VEGF and its receptors by myeloma cells. Leukemia 17:2025PubMedCrossRefGoogle Scholar
  52. 52.
    Moschos SJ, Mantzoros CS (2002) The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology 63:317PubMedCrossRefGoogle Scholar
  53. 53.
    Asosingh K, Radl J, Van Riet I, Van Camp B, Vanderkerken K (2000) The 5TMM series: a useful in vivo mouse model of human multiple myeloma. Hematol J 1:351PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Kai-Da Wu
    • 1
  • Li Zhou
    • 1
  • Douglas Burtrum
    • 2
  • Dale L. Ludwig
    • 2
  • Malcolm A. S. Moore
    • 1
  1. 1.James Ewing Laboratory of Developmental Hematopoiesis, Cell Biology ProgramMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.ImClone Systems IncorporatedNew YorkUSA

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