Advertisement

Medical Oncology

, 31:805 | Cite as

Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer

  • Pushpendra Singh
  • Jimi Marin Alex
  • Felix Bast
Review Article

Abstract

Insulin and insulin-like growth factor (IGF) signaling system, commonly known for fine-tuning numerous biological processes, has lately made its mark as a much sought-after therapeutic targets for diabetes and cancer. These receptors make an attractive anticancer target owing to their overexpression in variety of cancer especially in prostate and breast cancer. Inhibitors of IGF signaling were subjected to clinical cancer trials with the main objective to confirm the effectiveness of these receptors as a therapeutic target. However, the results that these trials produced proved to be disappointing as the role played by the cross talk between IGF and insulin receptor (IR) signaling pathways at the receptor level or at downstream signaling level became more lucid. Therapeutic strategy for IGF-1R and IR inhibition mainly encompasses three main approaches namely receptor blockade with monoclonal antibodies, tyrosine kinase inhibition (ATP antagonist and non-ATP antagonist), and ligand neutralization via monoclonal antibodies targeted to ligand or recombinant IGF-binding proteins. Other drug-discovery approaches are employed to target IGF-1R, and IR includes antisense oligonucleotides and recombinant IGF-binding proteins. However, therapies with monoclonal antibodies and tyrosine kinase inhibition targeting the IGF-1R are not evidenced to be satisfactory as expected. Factors that are duly held responsible for the unsuccessfulness of these therapies include (a) the existence of the IR isoform A overexpressed on a variety of cancers, enhancing the mitogenic signals to the nucleus leading to the endorsement of cell growth, (b) IGF-1R and IR that form hybrid receptors sensitive to the stimulation of all three IGF axis ligands, and (c) IGF-1R and IR that also have the potential to form hybrid receptors with other tyrosine kinase to potentiate the cellular transformation, tumorigenesis, and tumor vascularization. This mini review is a concerted effort to explore and fathom the well-recognized roles of the IRA signaling system in human cancer phenotype and the main strategies that have been so far evaluated to target the IR and IGF-1R.

Keywords

Insulin receptor Insulin-like growth factor receptor Cancer Therapies 

Notes

Acknowledgments

We would like to thank Vice Chancellor, Central University of Punjab, Bathinda, Punjab, (India) for supporting this study with infrastructural requirements. We also thank Professor P. Ramarao (Dean, Academic Affairs) Central University of Punjab, Bathinda, Punjab, India, for his suggestions during the course that tremendously helped to improve this article. This study was also supported by a Senior Research Fellowship Grant-in-Aid from Indian Council of Medical Research (ICMR), Government of India awarded to PS.

Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this article.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Cancer J Clin. 2011;61:69–90.Google Scholar
  2. 2.
    Weiderpass E, Gridley G, Persson I, Nyrén O, Ekbom A, Adami HO. Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer. 1997;71:360–3.PubMedGoogle Scholar
  3. 3.
    Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol. 2005;6:103–11.PubMedGoogle Scholar
  4. 4.
    Bonovas S, Filioussi K, Tsantes A. Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia. 2004;47:1071–8.PubMedGoogle Scholar
  5. 5.
    Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prevent. 2006;15:2056–62.Google Scholar
  6. 6.
    Abreu-Martin MT, Chari A, Palladino AA, Craft NA, Sawyers CL. Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Mol Cell Biol. 1999;19:5143–54.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr-Relat Cancer. 2009;16:1103–23.PubMedGoogle Scholar
  8. 8.
    Vigneri P, Frasca F, Sciacca L, Frittitta L, Vigneri R. Obesity and cancer. Nutr Metab Cardiovasc Dis. 2006;16:1–7.PubMedGoogle Scholar
  9. 9.
    Fisher WE. Diabetes: risk factor for the development of pancreatic cancer or manifestation of the disease? World J Surg. 2001;25:503–8.PubMedGoogle Scholar
  10. 10.
    Strickler HD, Wylie-Rosett J, Rohan T, Hoover DR, Smoller S, Burk RD, Yu H. The relation of type 2 diabetes and cancer. Diabetes Technol Ther. 2001;3:263–74.PubMedGoogle Scholar
  11. 11.
    Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.PubMedGoogle Scholar
  12. 12.
    Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor I and risk of breast cancer. Lancet. 1998;351:1393–6.PubMedGoogle Scholar
  13. 13.
    Hsing AW, Sakoda LC, Chua SC. Obesity, metabolic syndrome, and prostate cancer. Am J Clin Nutr. 2007;86:843S–57S.Google Scholar
  14. 14.
    Tao Y, Pinzi V, Bourhis J, Deutsch E. Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer. Nat Rev Clin Oncol. 2007;4:591–602.Google Scholar
  15. 15.
    Djavan B, Waldert M, Seitz C, Marberger M. Insulin-like growth factors and prostate cancer. World J Urol. 2001;19:225–33.PubMedGoogle Scholar
  16. 16.
    Gualberto A, Pollak M. Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene. 2009;28:3009–21.PubMedGoogle Scholar
  17. 17.
    Rodon J, DeSantos V, Ferry RJ, Kurzrock R. Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials. Mol Cancer Ther. 2008;7:2575–88.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Zhang H, Fagan DH, Zeng X, Freeman KT, Sachdev D, Yee D. Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation. Oncogene. 2010;29:2517–27.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T. Adiponectin as a biomarker of the metabolic syndrome. Circ J. 2004;68:975.PubMedGoogle Scholar
  20. 20.
    Grundy M, Scott M. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol. 1998;81:18B–25B.PubMedGoogle Scholar
  21. 21.
    Nguyen NT, Magno CP, Lane KT, Hinojosa MW, Lane JS. Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004. J Am Coll Surg. 2008;207:928–34.PubMedGoogle Scholar
  22. 22.
    Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.PubMedGoogle Scholar
  23. 23.
    Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28.PubMedGoogle Scholar
  24. 24.
    Zhang H, Yee D. The therapeutic potential of agents targeting the type I insulin-like growth factor receptor. Expert Opin Inv Drugs. 2004;13:1569–77.Google Scholar
  25. 25.
    Hofmann F, García-Echeverría C. Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drug Discov Today. 2005;10:1041–8.PubMedGoogle Scholar
  26. 26.
    Gennigens C, Menetrier-Caux C, Droz J. Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol. 2006;58:124.PubMedGoogle Scholar
  27. 27.
    Huang J, Morehouse C, Streicher K, Higgs BW, Gao J, Czapiga M, Boutrin A, Zhu W, Brohawn P, Chang Y. Altered expression of insulin receptor isoforms in breast cancer. PLoS ONE. 2011;6:e26177.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Heni M, Hennenlotter J, Scharpf M, Lutz SZ, Schwentner C, Todenhöfer T, Schilling D, Kühs U, Gerber V, Machicao F. Insulin receptor isoforms A and B as well as insulin receptor substrates-1 and 2 are differentially expressed in prostate cancer. PLoS ONE. 2012;7:e50953.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.PubMedGoogle Scholar
  30. 30.
    Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A. Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway. Endocrinology. 2012;153:2152–63.PubMedGoogle Scholar
  31. 31.
    Dupont J, Holzenberger M. Biology of insulin like growth factors in development. Birth Defects Res C Embryo Today. 2003;69:257–71.PubMedGoogle Scholar
  32. 32.
    Xu G, Marshall CA, Lin TA, Kwon G, Munivenkatappa RB, Hill JR, Lawrence JC. McDaniel ML Insulin mediates glucose-stimulated phosphorylation of PHAS-I by pancreatic beta cells. J Biol Chem. 1998;273:4485.PubMedGoogle Scholar
  33. 33.
    Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007;6:1–12.PubMedGoogle Scholar
  34. 34.
    Duan C, Xu Q. Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions. Gen Comp Endocrinol. 2005;142:44–52.PubMedGoogle Scholar
  35. 35.
    De Meyts P, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov. 2002;1:769–83.PubMedGoogle Scholar
  36. 36.
    Beauchamp M-C, Yasmeen A, Knafo A, Gotlieb WH. Targeting insulin and insulin-like growth factor pathways in epithelial ovarian cancer. J Oncol. 2010. doi: 10.1155/2010/257058.
  37. 37.
    LeRoith D, Roberts CT. The insulin-like growth factor system and cancer. Cancer Lett. 2003;195:127–37.PubMedGoogle Scholar
  38. 38.
    Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocrine Rev. 1999;20:761–87.Google Scholar
  39. 39.
    Baxter RC. Insulin-like growth factor binding proteins in the human circulation: a review. Horm Res Paediatr. 1994;42:140–4.Google Scholar
  40. 40.
    Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363:1346–53.PubMedGoogle Scholar
  41. 41.
    Jerome L, Alami N, Belanger S, Page V, Yu Q, Paterson J, Shiry L, Pegram M, Leyland-Jones B. Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates Herceptin activity in vivo. Cancer Res. 2006;66:7245–52.PubMedGoogle Scholar
  42. 42.
    Nahta R, Yu D, Hung M-C, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Rev Clin Oncol. 2006;3:269–80.Google Scholar
  43. 43.
    Fuller GN, Rhee CH, Hess KR, Caskey LS, Wang R, Bruner JM, Yung WA, Zhang W. Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme a revelation by parallel gene expression profiling. Cancer Res. 1999;59:4228–32.PubMedGoogle Scholar
  44. 44.
    Busund L, Richardsen E, Busund R, Ukkonen T, Bjørnsen T, Busch C, Stalsberg H. Significant expression of IGFBP2 in breast cancer compared with benign lesions. J Clin Pathol. 2005;58:361–6.PubMedGoogle Scholar
  45. 45.
    Wang H, Wang H, Shen W, Huang H, Hu L, Ramdas L, Zhou Y-H, Liao WS, Fuller GN, Zhang W. Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res. 2003;63:4315–21.PubMedGoogle Scholar
  46. 46.
    Dupont J, LeRoith D. Insulin and insulin-like growth factor I receptors: similarities and differences in signal transduction. Horm Res Paediatr. 2000;55:22–6.Google Scholar
  47. 47.
    Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S, Belfiore A, Vigneri R. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem. 2008;114:23–37.PubMedGoogle Scholar
  48. 48.
    Kuijjer ML, Peterse EF, van den Akker BE, Briaire-de Bruijn IH, Serra M, Meza-Zepeda LA, Myklebost O, Hassan AB, Hogendoorn PC, Cleton-Jansen A-M. IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma. BMC Cancer. 2013;13:245.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Vella V, Sciacca L, Pandini G, Mineo R, Squatrito S, Vigneri R, Belfiore A. The IGF system in thyroid cancer: new concepts. Mol Pathol. 2001;54:121–4.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Pandini G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y, Siddle K, Goldfine ID, Belfiore A. Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res. 1999;5:1935–44.PubMedGoogle Scholar
  51. 51.
    Cox ME, Gleave ME, Zakikhani M, Bell RH, Piura E, Vickers E, Cunningham M, Larsson O, Fazli L, Pollak M. Insulin receptor expression by human prostate cancers. Prostate. 2009;69:33–40.PubMedGoogle Scholar
  52. 52.
    Werner H, Weinstein D, Bentov I. Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Arch Physiol Biochem. 2008;114:17–22.PubMedGoogle Scholar
  53. 53.
    Kissau L, Stahl P, Mazitschek R, Giannis A, Waldmann H. Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold. J Med Chem. 2003;46:2917–31.PubMedGoogle Scholar
  54. 54.
    Denley A, Bonython ER, Booker GW, Cosgrove LJ, Forbes BE, Ward CW, Wallace JC. Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol Endocrinol. 2004;18:2502–12.PubMedGoogle Scholar
  55. 55.
    Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev. 2005;16:421–39.PubMedGoogle Scholar
  56. 56.
    Zhang H, Pelzer AM, Kiang DT, Yee D. Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin. Cancer Res. 2007;67:391–7.PubMedGoogle Scholar
  57. 57.
    Pierre-Eugene C, Pagesy P, Nguyen TT, Neuillé M, Tschank G, Tennagels N, Hampe C. Issad T Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2. PLoS ONE. 2012;7:e41992.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Blanquart C, Achi J, Issad T. Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer. Biochem Pharmacol. 2008;76:873–83.PubMedGoogle Scholar
  59. 59.
    Sherajee SJ, Fujita Y, Rafiq K, Nakano D, Mori H, Masaki T, Hara T, Kohno M, Nishiyama A, Hitomi H. Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor. Arterioscler Thromb Vasc Biol. 2012;32:257–63.PubMedGoogle Scholar
  60. 60.
    Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002;277:39684–95.PubMedGoogle Scholar
  61. 61.
    Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocrine Rev. 2009;30:586.Google Scholar
  62. 62.
    Mamula PW, McDonald AR, Brunetti A, Okabayashi Y, Wong KY, Maddux BA, Logsdon C, Goldfine ID. Regulating insulin-receptor-gene expression by differentiation and hormones. Diabetes Care. 1990;13:288–301.PubMedGoogle Scholar
  63. 63.
    Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114:63–70.PubMedGoogle Scholar
  64. 64.
    Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, Beaulieu F, Chang C, Clarke W, Dell J. Discovery of a 1 H-Benzoimidazol-2-yl)-1 H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J Med Chem. 2005;48:5639–43.PubMedGoogle Scholar
  65. 65.
    Beauchamp M-C, Knafo A, Yasmeen A, Carboni JM, Gottardis MM, Pollak MN, Gotlieb WH. BMS-536924 sensitizes human epithelial ovarian cancer cells to the PARP inhibitor, 3-aminobenzamide. Gynecol Oncol. 2009;115:193–8.PubMedGoogle Scholar
  66. 66.
    Velaparthi U, Saulnier MG, Wittman MD, Liu P, Frennesson DB, Zimmermann K, Carboni JM, Gottardis M, Li A, Greer A. Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors: SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one. Bioorg Med Chem Lett. 2010;20:3182–5.PubMedGoogle Scholar
  67. 67.
    Avnet S, Sciacca L, Salerno M, Gancitano G, Cassarino MF, Longhi A, Zakikhani M, Carboni JM, Gottardis M, Giunti A. Insulin receptor isoform A and insulin-like growth factor II as additional treatment targets in human osteosarcoma. Cancer Res. 2009;69:2443–52.PubMedGoogle Scholar
  68. 68.
    Hendrickson AEW, Haluska P, Schneider PA, Loegering DA, Peterson KL, Attar R, Smith BD, Erlichman C, Gottardis M, Karp JE. Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro. Cancer Res. 2009;69:7635–43.PubMedCentralGoogle Scholar
  69. 69.
    Dool CJ, Mashhedi H, Zakikhani M, David S, Zhao Y, Birman E, Carboni JM, Gottardis M, Blouin M-J, Pollak M. IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer. Endocr Relat Cancer. 2011;18:699–709.PubMedGoogle Scholar
  70. 70.
    Huang F, Greer A, Hurlburt W, Han X, Hafezi R, Wittenberg GM, Reeves K, Chen J, Robinson D, Li A. The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res. 2009;69:161–70.PubMedGoogle Scholar
  71. 71.
    Jin Q, Esteva FJ. Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:485–98.PubMedGoogle Scholar
  72. 72.
    Litzenburger BC, Creighton CJ, Tsimelzon A, Chan BT, Hilsenbeck SG, Wang T, Carboni JM, Gottardis MM, Huang F, Chang JC. High IGF-IR activity in triple-negative breast cancer cell lines and tumorgrafts correlates with sensitivity to anti-IGF-IR therapy. Clin Cancer Res. 2011;17:2314–27.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Wittman MD, Carboni JM, Yang Z, Lee FY, Antman M, Attar R, Balimane P, Chang C, Chen C, Discenza L. Discovery of a 2,4-disubstituted pyrrolo [1,2-f][1,2,4] triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem. 2009;52:7360–3.PubMedGoogle Scholar
  74. 74.
    Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009;8:3341–9.PubMedGoogle Scholar
  75. 75.
    Huang F, Hurlburt W, Greer A, Reeves KA, Hillerman S, Chang H, Fargnoli J, Finckenstein FG, Gottardis MM, Carboni JM. Differential mechanisms of acquired resistance to insulin-like growth factor-I receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 2010;70:7221–31.PubMedGoogle Scholar
  76. 76.
    Hou X, Huang F, Macedo LF, Harrington SC, Reeves KA, Greer A, Finckenstein FG, Brodie A, Gottardis MM, Carboni JM. Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer. Cancer Res. 2011;71:7597–607.PubMedGoogle Scholar
  77. 77.
    Dinchuk JE, Cao C, Huang F, Reeves KA, Wang J, Myers F, Cantor GH, Zhou X, Attar RM, Gottardis M. Insulin receptor (IR) pathway hyperactivity in IGF-IR null cells and suppression of downstream growth signaling using the dual IGF-IR/IR inhibitor, BMS-754807. Endocrinology. 2010;151:4123–32.PubMedGoogle Scholar
  78. 78.
    Kolb EA, Gorlick R, Lock R, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C. Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2011;56:595–603.PubMedGoogle Scholar
  79. 79.
    Desai J, Solomon B, Davis I, Lipton L, Hicks R, Scott A, Park J, Clemens P, Gestone T, Finckenstein F. Phase I dose-escalation study of daily BMS-754807, an oral, dual IGF-1R/insulin receptor (IR) inhibitor in subjects with solid tumors. J Clin Oncol. 2010;28:15s, abstr 3104.Google Scholar
  80. 80.
    Levitzki A, Mishani E. Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem. 2006;75:93–109.PubMedGoogle Scholar
  81. 81.
    Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C, Levitzki A. Tyrphostins. II. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J Med Chem. 1991;34:1896–907.PubMedGoogle Scholar
  82. 82.
    Davoodi-Semiromi A, Wasserfall CH, Xia CQ, Cooper-DeHoff RM, Wabitsch M, Clare-Salzler M, Atkinson M. The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice. PLoS ONE. 2012;7:e36079.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O’Connor M, Pirritt C, Sun Y, Yao Y. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem. 2009;1:1153–71.PubMedGoogle Scholar
  84. 84.
    King ER, Wong K–K. Insulin-like growth factor: current concepts and new developments in cancer therapy. Recent Pat Anti-Cancer Drug Discov. 2012;7:14–30.Google Scholar
  85. 85.
    Pitts TM, Tan AC, Kulikowski GN, Tentler JJ, Brown AM, Flanigan SA, Leong S, Coldren CD, Hirsch FR, Varella-Garcia M. Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development. Clin Cancer Res. 2010;16:3193–204.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Buck E, Gokhale PC, Koujak S, Brown E, Eyzaguirre A, Tao N, Lerner L, Chiu MI, Wild R, Epstein D. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol Cancer Ther. 2010;9:2652–64.PubMedGoogle Scholar
  87. 87.
    Zeng X, Zhang H, Oh A, Zhang Y, Yee D. Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor. Breast Cancer Res Treat. 2012;133:117–26.PubMedGoogle Scholar
  88. 88.
    King ER, Zu Z, Tsang Y, Deavers MT, Malpica A, Mok SC, Gershenson DM, Wong K–K. The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma. Gynecol Oncol. 2011;123:13–8.PubMedCentralPubMedGoogle Scholar
  89. 89.
    McKinley ET, Bugaj JE, Zhao P, Guleryuz S, Mantis C, Gokhale PC, Wild R, Manning HC. 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer. Clin Cancer Res. 2011;17:3332–40.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Flanigan SA, Pitts TM, Eckhardt SG, Tentler JJ, Tan AC, Thorburn A, Leong S. The insulin-like growth factor I receptor/insulin receptor tyrosine kinase inhibitor PQIP exhibits enhanced antitumor effects in combination with chemotherapy against colorectal cancer models. Clin Cancer Res. 2010;16:5436–46.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Haluska P, Carboni JM, Loegering DA, Lee FY, Wittman M, Saulnier MG, Frennesson DB, Kalli KR, Conover CA, Attar RM. In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res. 2006;66:362–71.PubMedGoogle Scholar
  92. 92.
    Ekman S, Frödin J-E, Harmenberg J, Bergman A, Hedlund Å, Dahg P, Alvfors C, Ståhl B, Bergström S, Bergqvist M. Clinical phase I study with an insulin-like growth factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma. Acta Oncol. 2011;50:441–7.PubMedGoogle Scholar
  93. 93.
    Scagliotti GV, Novello S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev. 2012;38:292–302.PubMedGoogle Scholar
  94. 94.
    Girnita A, All-Ericsson C, Economou MA, Axelson M, Seregard S, Larsson O, Girnita L. The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Clin Cancer Res. 2006;12:1383–91.PubMedGoogle Scholar
  95. 95.
    Menu E, Jernberg-Wiklund H, Stromberg T, De Raeve H, Girnita L, Larsson O, Axelson M, Asosingh K, Nilsson K, Van Camp B. Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model. Blood. 2006;107:655–60.PubMedGoogle Scholar
  96. 96.
    Feng X, Aleem E, Lin Y, Axelson M, Larsson O, Strömberg T. Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: clinical implications. Int J Oncol. 2012;40:1251.PubMedGoogle Scholar
  97. 97.
    García-Echeverría C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro H-G, Cozens R. In vivo antitumor activity of NVP-AEW541, a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell. 2004;5:231–9.PubMedGoogle Scholar
  98. 98.
    Scotlandi K, Manara MC, Nicoletti G, Lollini P-L, Lukas S, Benini S, Croci S, Perdichizzi S, Zambelli D, Serra M. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res. 2005;65:3868–76.PubMedGoogle Scholar
  99. 99.
    Tanno B, Mancini C, Vitali R, Mancuso M, McDowell HP, Dominici C, Raschellà G. Down-regulation of insulin-like growth factor I receptor activity by NVP-AEW541 has an antitumor effect on neuroblastoma cells in vitro and in vivo. Clin Cancer Res. 2006;12:6772–80.PubMedGoogle Scholar
  100. 100.
    Tazzari P, Tabellini G, Bortul R, Papa V, Evangelisti C, Grafone T, Martinelli G, McCubrey J, Martelli A. The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion. Leukemia. 2007;21:886–96.PubMedGoogle Scholar
  101. 101.
    Mukohara T, Shimada H, Ogasawara N, Wanikawa R, Shimomura M, Nakatsura T, Ishii G, Park JO, Jänne PA, Saijo N. Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependent on the level of IRS-1 expression. Cancer Lett. 2009;282:14–24.PubMedGoogle Scholar
  102. 102.
    Maiso P, Ocio EM, Garayoa M, Montero JC, Hofmann F, García-Echeverría C, Zimmermann J, Pandiella A, San Miguel JF. The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells. Brit J Haematol. 2008;141:470–82.Google Scholar
  103. 103.
    Gariboldi MB, Ravizza R, Monti E. The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells. Biochem Pharmacol. 2010;80:455–62.PubMedGoogle Scholar
  104. 104.
    Baumann P, Hagemeier H, Mandl-Weber S, Franke D, Schmidmaier R. Myeloma cell growth inhibition is augmented by synchronous inhibition of the insulin-like growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian target of rapamycin by Rad001. Anticancer Drugs. 2009;20:259–66.PubMedGoogle Scholar
  105. 105.
    Moser C, Schachtschneider P, Lang SA, Gaumann A, Mori A, Zimmermann J, Schlitt HJ, Geissler EK, Stoeltzing O. Inhibition of insulin-like growth factor-I receptor (IGF-IR) using NVP-AEW541, a small molecule kinase inhibitor, reduces orthotopic pancreatic cancer growth and angiogenesis. Eur J Cancer. 2008;44:1577–86.PubMedGoogle Scholar
  106. 106.
    Wolf S, Lorenz J, Mössner J, Wiedmann M. Treatment of biliary tract cancer with NVP-AEW541: mechanisms of action and resistance. World J Gastroenterol. 2010;16:156.PubMedGoogle Scholar
  107. 107.
    Tarn C, Rink L, Merkel E, Flieder D, Pathak H, Koumbi D, Testa JR, Eisenberg B, von Mehren M, Godwin AK. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci USA. 2008;105:8387–92.PubMedGoogle Scholar
  108. 108.
    Manara MC, Landuzzi L, Nanni P, Nicoletti G, Zambelli D, Lollini PL, Nanni C, Hofmann F, García-Echeverría C, Picci P. Preclinical in vivo study of new insulin-like growth factor-I receptor-specific inhibitor in Ewing’s sarcoma. Clin Cancer Res. 2007;13:1322–30.PubMedGoogle Scholar
  109. 109.
    Barlaskar FM, Spalding AC, Heaton JH, Kuick R, Kim AC, Thomas DG, Giordano TJ, Ben-Josef E, Hammer GD. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab. 2009;94:204–10.PubMedGoogle Scholar
  110. 110.
    Gotlieb WH, Bruchim I, Gu J, Shi Y, Camirand A, Blouin M-J, Zhao Y, Pollak MN. Insulin-like growth factor receptor I targeting in epithelial ovarian cancer. Gynecol Oncol. 2006;100:389–96.PubMedGoogle Scholar
  111. 111.
    Hägerstrand D, Lindh MB, Peña C, Garcia-Echeverria C, Nistér M, Hofmann F, Östman A. PI3 K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541. Neuro-Oncology. 2010;12:967–75.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Martins AS, Mackintosh C, Martín DH, Campos M, Hernández T, Ordóñez J-L, de Alava E. Insulin-like growth factor I receptor pathway inhibition by ADW742, alone or in combination with imatinib, doxorubicin, or vincristine, is a novel therapeutic approach in Ewing tumor. Clin Cancer Res. 2006;12:3532–40.PubMedGoogle Scholar
  113. 113.
    Scotlandi K, Manara MC, Hattinger CM, Benini S, Perdichizzi S, Pasello M, Bacci G, Zanella L, Bertoni F, Picci P. Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing’s sarcoma. Eur J Cancer. 2005;41:1349–61.PubMedGoogle Scholar
  114. 114.
    Lu D, Jimenez X, Zhang H, Atkins A, Brennan L, Balderes P, Bohlen P, Witte L, Zhu Z. Di-diabody: a novel tetravalent bispecific antibody molecule by design. J Immunol Methods. 2003;279:219–32.PubMedGoogle Scholar
  115. 115.
    Kontermann RE. Recombinant bispecific antibodies for cancer therapy. Acta Pharmacol Sinica. 2005;26:1–9.Google Scholar
  116. 116.
    Deyev SM, Lebedenko EN. Multivalency: the hallmark of antibodies used for optimization of tumor targeting by design. BioEssays. 2008;30:904–18.PubMedGoogle Scholar
  117. 117.
    Hartog H, Wesseling J, Boezen HM, van der Graaf WT. The insulin-like growth factor 1 receptor in cancer: old focus, new future. Eur J Cancer. 2007;43:1895–904.PubMedGoogle Scholar
  118. 118.
    Ozkan EE. Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: a review. Mol Cell Endocrinol. 2011;344:1–24.PubMedGoogle Scholar
  119. 119.
    Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov. 2009;4:54–72.PubMedGoogle Scholar
  120. 120.
    Maloney EK, McLaughlin JL, Dagdigian NE, Garrett LM, Connors KM, Zhou X-M, Blättler WA, Chittenden T, Singh R. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res. 2003;63:5073–83.PubMedGoogle Scholar
  121. 121.
    Zeng X, Sachdev D, Zhang H, Gaillard-Kelly M, Yee D. Sequencing of type I insulin-like growth factor receptor inhibition affects chemotherapy response in vitro and in vivo. Clin Cancer Res. 2009;15:2840–9.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Geoerger B, Brasme J-F, Daudigeos-Dubus E, Opolon P, Venot C, Debussche L, Vrignaud P, Vassal G. Anti-insulin-like growth factor 1 receptor antibody EM164 (murine AVE1642) exhibits anti-tumour activity alone and in combination with temozolomide against neuroblastoma. Eur J Cancer. 2010;46:3251–62.PubMedGoogle Scholar
  123. 123.
    Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H. 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. 2003;63:8912–21.PubMedGoogle Scholar
  124. 124.
    Rowinsky EK, Youssoufian H, Tonra JR, Solomon P, Burtrum D, Ludwig DL. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res. 2007;13:5549–55.Google Scholar
  125. 125.
    Wu K-D, Zhou L, Burtrum D, Ludwig DL, Moore MA. 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. 2007;56:343–57.PubMedGoogle Scholar
  126. 126.
    Wu JD, Odman A, Higgins LM, Haugk K, Vessella R, Ludwig DL, Plymate SR. In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res. 2005;11:3065–74.PubMedGoogle Scholar
  127. 127.
    Wu JD, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P, Montgomery RB, Ludwig DL, Plymate SR. Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors. Clin Cancer Res. 2006;12:6153–60.PubMedGoogle Scholar
  128. 128.
    Haluska P, Worden F, Olmos D, Yin D, Schteingart D, Batzel GN, Paccagnella ML, de Bono JS, Gualberto A, Hammer GD. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol. 2010;65:765–73.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Gualberto A, Karp DD. Development of the monoclonal antibody Figitumumab, targeting the insulin-like growth factor-1 receptor, for the treatment of patients with non-small-cell lung cancer. Clin Lung Cancer. 2009;10:273–80.PubMedGoogle Scholar
  130. 130.
    Olmos D, Postel-Vinay S, Molife L, Okuno SH, Schuetze SM, Paccagnella ML, Batzel GN, Yin D, Pritchard-Jones K, Judson I. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing’s sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 2010;11:129–35.PubMedCentralPubMedGoogle Scholar
  131. 131.
    O’Neill A, Shah N, Zitomersky N, Ladanyi M, Shukla N, Üren A, Loeb D, Toretsky J. Insulin-like growth factor 1 receptor as a therapeutic target in Ewing Sarcoma: lack of consistent upregulation or recurrent mutation and a review of the clinical trial literature. Sarcoma. 2013.Google Scholar
  132. 132.
    Quek R, Wang Q, Morgan JA, Shapiro GI, Butrynski JE, Ramaiya N, Huftalen T, Jederlinic N, Manola J, Wagner AJ. Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res. 2011;17:871–9.PubMedGoogle Scholar
  133. 133.
    Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS, Ludwig J, Chen HX, Doyle LA, Kurzrock R. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res. 2012;18:2625–31.PubMedGoogle Scholar
  134. 134.
    Hixon ML, Paccagnella L, Millham R, Perez-Olle R, Gualberto A. Development of inhibitors of the IGF-IR/PI3 K/Akt/mTOR pathway. Rev Recent Clin Trials. 2010;5:189–208.PubMedGoogle Scholar
  135. 135.
    Javle M, Varadhachary G, Bhosale P, Ukegbu L, Overman M, Shroff R. Phase I study of MK-0646, a humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine plus erlotinib (E) for advanced previously untreated pancreatic cancer. ASCO gastrointestinal cancers symposium (abstract 131), 2010.Google Scholar
  136. 136.
    Watkins D, Tabernero J, Schmoll H, Trarbach T, Ramos F, Hsu K, Gates M, Clark J, LeVan P, Cunningham D. A phase II study of the anti-IGFR antibody MK-0646 in combination with cetuximab and irinotecan in the treatment of chemorefractory metastatic colorectal cancer. J Clin Oncol. 2009;27:15s, abstr 4127.Google Scholar
  137. 137.
    Bao XH, Naomoto Y, Hao HF, Watanabe N, Sakurama K, Noma K, Motoki T, Tomono Y, Fukazawa T, Shirakawa Y. IGF-IR and its inhibitors in gastrointestinal carcinomas (Review). Oncol Lett. 2010;1:195–201.PubMedCentralPubMedGoogle Scholar
  138. 138.
    Atzori F, Tabernero J, Cervantes A, Prudkin L, Andreu J, Rodríguez-Braun E, Domingo A, Guijarro J, Gamez C, Rodon J. A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2011;17:6304–12.PubMedGoogle Scholar
  139. 139.
    Javle M, Varadhachary G, Shroff R, Bhosale P, Overman M, Weatherly J, Wolff R, Abbruzzese J. Phase I/II study of MK-0646, the humanized monoclonal IGF-1R antibody in combination with gemcitabine or gemcitabine plus erlotinib (E) for advanced pancreatic cancer. J Clin Oncol. 2010; meeting abstr 4039.Google Scholar
  140. 140.
    Wang Y, Hailey J, Williams D, Wang Y, Lipari P, Malkowski M, Wang X, Xie L, Li G, Saha D. Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. Mol Cancer Ther. 2005;4:1214–21.PubMedGoogle Scholar
  141. 141.
    Wang Y, Ji Q-s, Mulvihill M, Pachter JA. Inhibition of the IGF-I receptor for treatment of cancer. Kinase inhibitors and monoclonal antibodies as alternative approaches. In: Targeted interference with signal transduction events. Recent results in cancer research, vol. 17, 2007. p. 59–76.Google Scholar
  142. 142.
    Kolb EA, Gorlick R, Houghton PJ, Morton CL, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50:1190–7.PubMedGoogle Scholar
  143. 143.
    Wang X, Lipari P, Liu L, Long B, Liu J, Ramos R, Hailey J, Mayer-Ezell R, Wang L, Maxwell E. Efficacy of human anti-IGF-1R antibody in tumor xenograft models as a single agent and in combination with anti-cancer drugs. AACR Meeting Abstracts, 2005, p. 1190.Google Scholar
  144. 144.
    Wang Y, Hailey J, Williams D, Wang Y, Lipari P, Malkowski M, Wang X, Xie L, Li G, Saha D. Inhibition of IGF-1R signaling and tumor cell proliferation by a fully human neutralizing anti-IGF-1R antibody. In: Proceedings of the American Association for Cancer Research 2005:1190.Google Scholar
  145. 145.
    Ohtani M, Numazaki M, Yajima Y, Fujita-Yamaguchi Y. Mechanisms of antibody-mediated insulin-like growth factor I receptor (IGF-IR) down-regulation in MCF-7 breast cancer cells. Biosci Trends. 2009;3:131.PubMedGoogle Scholar
  146. 146.
    Li S-L, Liang S-J, Guo N, Wu AM, Fujita-Yamaguchi Y. Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumor growth. Cancer Immunol Immunother. 2000;49:243–52.PubMedGoogle Scholar
  147. 147.
    Fujita-Yamaguchi Y. Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumor growth. In: Google Patents. 2002.Google Scholar
  148. 148.
    Ye J–J, Liang S-J, Guo N, Li S-L, Wu A, Giannini S, Sachdev D, Yee D, Brünner N, Ikle D. 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. 2003;35:836–42.PubMedGoogle Scholar
  149. 149.
    Sachdev D, Li S-L, Hartell JS, Fujita-Yamaguchi Y, Miller JS, Yee D. A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. Cancer Res. 2003;63:627–35.PubMedGoogle Scholar
  150. 150.
    Schäffer L, Brissette RE, Spetzler JC, Pillutla RC, Østergaard S, Lennick M, Brandt J, Fletcher PW, Danielsen GM, Hsiao K-C. Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks. Proc Natl Acad Sci USA. 2003;100:4435–9.PubMedGoogle Scholar
  151. 151.
    Knudsen L, Hansen BF, Jensen P, Pedersen TÅ, Vestergaard K, Schäffer L, Blagoev B, Oleksiewicz MB, Kiselyov VV, De Meyts P. Agonism and antagonism at the insulin receptor. PLoS ONE. 2012;7:e51972.PubMedCentralPubMedGoogle Scholar
  152. 152.
    Soos M, Siddle K, Baron MD, Heward JM, Luzio JP, Bellatin J, Lennox ES. Monoclonal antibodies reacting with multiple epitopes on the human insulin receptor. Biochem J. 1986;235:199–208.PubMedGoogle Scholar
  153. 153.
    Schäffer L, Brand CL, Hansen BF, Ribel U, Shaw AC, Slaaby R, Sturis J. A novel high-affinity peptide antagonist to the insulin receptor. Biochem Biophys Res Commun. 2008;376:380–3.PubMedGoogle Scholar
  154. 154.
    Vikram A, Jena G. S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats. Biochem Biophys Res Commun. 2010;398:260–5.PubMedGoogle Scholar
  155. 155.
    Miyamoto S, Nakamura M, Shitara K, Nakamura K, Ohki Y, Ishii G, Goya M, Kodama K, Sangai T, Maeda H. Blockade of paracrine supply of insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers. Clin Cancer Res. 2005;11:3494–502.PubMedGoogle Scholar
  156. 156.
    Goya M, Miyamoto S, Nagai K, Ohki Y, Nakamura K, Shitara K, Maeda H, Sangai T, Kodama K, Endoh Y. Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors. Cancer Res. 2004;64:6252–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Pushpendra Singh
    • 1
  • Jimi Marin Alex
    • 2
  • Felix Bast
    • 1
  1. 1.Centre for Biosciences, School of Basic and Applied ScienceCentral University of PunjabBathindaIndia
  2. 2.Centre for Chemical and Pharmaceutical Sciences, School of Basic and Applied ScienceCentral University of PunjabBathindaIndia

Personalised recommendations