Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Kyle RA, Rajkumar SV (2004) Multiple myeloma. N Engl J Med 351:1860

    Article  PubMed  CAS  Google Scholar 

  2. Mitsiades CS, Mitsiades N, Munshi NC, Anderson KC (2004) Focus on multiple myeloma. Cancer Cell 6:439

    Article  PubMed  CAS  Google Scholar 

  3. Barlogie B, Shaughnessy J, Tricot G, Jacobson J, Zangari M, Anaissie E, Walker R, Crowley J (2004) Treatment of multiple myeloma. Blood 103:20

    Article  PubMed  CAS  Google Scholar 

  4. Fassas A, Shaughnessy J, Barlogie B (2005) Cure of myeloma: hype or reality? Bone Marrow Transplant 35:215

    Article  PubMed  CAS  Google Scholar 

  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 24:3121

    Article  PubMed  CAS  Google Scholar 

  6. Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505

    Article  PubMed  CAS  Google Scholar 

  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 95:2086

    Article  PubMed  CAS  Google Scholar 

  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 62:2942

    PubMed  CAS  Google Scholar 

  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 183:412

    Article  PubMed  CAS  Google Scholar 

  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 77:567

    Article  PubMed  CAS  Google Scholar 

  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 55:2007

    PubMed  CAS  Google Scholar 

  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 50:48

    PubMed  CAS  Google Scholar 

  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 53:3399

    PubMed  CAS  Google Scholar 

  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 181:145

    PubMed  CAS  Google Scholar 

  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 54:2803

    PubMed  CAS  Google Scholar 

  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 56:1761

    PubMed  CAS  Google Scholar 

  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 279:563

    Article  PubMed  CAS  Google Scholar 

  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 91:620

    Article  PubMed  CAS  Google Scholar 

  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 91:151

    Article  PubMed  CAS  Google Scholar 

  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 351:1393

    Article  PubMed  CAS  Google Scholar 

  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:F105

    PubMed  CAS  Google Scholar 

  22. Navarro M, Baserga R (2001) Limited redundancy of survival signals from the type 1 insulin-like growth factor receptor. Endocrinology 142:1073

    Article  PubMed  CAS  Google Scholar 

  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 54:3179

    PubMed  CAS  Google Scholar 

  24. Ge NL, Rudikoff S (2000) Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood 96:2856

    PubMed  CAS  Google Scholar 

  25. Carroll M, Abrams CS (2004) Signaling, drugs and apoptosis of myeloma cells. Cancer Biol Ther 3:195

    PubMed  CAS  Google Scholar 

  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 103:2291

    Article  PubMed  CAS  Google Scholar 

  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 44:543

    Article  PubMed  CAS  Google Scholar 

  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 99:4138

    Article  PubMed  CAS  Google Scholar 

  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 2:170

    Article  PubMed  CAS  Google Scholar 

  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 63:5850

    PubMed  CAS  Google Scholar 

  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 103:301

    Article  PubMed  CAS  Google Scholar 

  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 63:8912

    PubMed  CAS  Google Scholar 

  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 11:3065

    Article  PubMed  CAS  Google Scholar 

  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 93:235

    PubMed  CAS  Google Scholar 

  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 22:327

    Article  PubMed  CAS  Google Scholar 

  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 103:301

    Article  PubMed  CAS  Google Scholar 

  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 35:836

    Article  PubMed  CAS  Google Scholar 

  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 5:221

    Article  PubMed  CAS  Google Scholar 

  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 60:3909

    PubMed  CAS  Google Scholar 

  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 8:1993

    PubMed  CAS  Google Scholar 

  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 8:3259

    PubMed  CAS  Google Scholar 

  42. Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3

    Article  PubMed  CAS  Google Scholar 

  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 30:1128

    Article  PubMed  CAS  Google Scholar 

  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 90:1076

    Article  PubMed  CAS  Google Scholar 

  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 73:311

    Article  PubMed  CAS  Google Scholar 

  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 98:492

    Article  PubMed  CAS  Google Scholar 

  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 8:841

    PubMed  CAS  Google Scholar 

  48. Rafii S, Lyden D (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9:702

    Article  PubMed  CAS  Google Scholar 

  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 17:1961

    Article  PubMed  CAS  Google Scholar 

  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 98:428

    Article  PubMed  CAS  Google Scholar 

  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 17:2025

    Article  PubMed  CAS  Google Scholar 

  52. Moschos SJ, Mantzoros CS (2002) The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology 63:317

    Article  PubMed  CAS  Google Scholar 

  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 1:351

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Kang Zhang for excellent assistance with NOD-SCID mouse model, WeiHong Yang for performing the paraffin block and immunohistochemical staining on tumor sections, Katia Manova at the Molecular Cytology Core Facility for reviewing pathological slides, Pat Zanzonico at Animal Imaging Core for helping whole mouse bioimaging, and Kate deBeer for preparing the manuscript. M.A.S.M was supported by a SCOR Grant in Multiple Myeloma (Selina Chen-Kiang PI). This work was further supported by a translational grant from the LSA to M.A.S.M.

Author information

Authors and Affiliations

  1. James Ewing Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Kai-Da Wu, Li Zhou & Malcolm A. S. Moore

  2. ImClone Systems Incorporated, New York, NY, 10014, USA

    Douglas Burtrum & Dale L. Ludwig

Authors
  1. Kai-Da Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas Burtrum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dale L. Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Malcolm A. S. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Malcolm A. S. Moore.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, KD., Zhou, L., Burtrum, D. et al. 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 . Cancer Immunol Immunother 56, 343–357 (2007). https://doi.org/10.1007/s00262-006-0196-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0196-9

Keywords

Search

Navigation