Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review Article
  • Published:
Medical Oncology Aims and scope Submit manuscript

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.

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

Similar content being viewed by others

References

  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. 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.

    CAS  PubMed  Google Scholar 

  3. Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol. 2005;6:103–11.

    CAS  PubMed  Google Scholar 

  4. Bonovas S, Filioussi K, Tsantes A. Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia. 2004;47:1071–8.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr-Relat Cancer. 2009;16:1103–23.

    CAS  PubMed  Google Scholar 

  8. Vigneri P, Frasca F, Sciacca L, Frittitta L, Vigneri R. Obesity and cancer. Nutr Metab Cardiovasc Dis. 2006;16:1–7.

    CAS  PubMed  Google Scholar 

  9. Fisher WE. Diabetes: risk factor for the development of pancreatic cancer or manifestation of the disease? World J Surg. 2001;25:503–8.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  11. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  13. Hsing AW, Sakoda LC, Chua SC. Obesity, metabolic syndrome, and prostate cancer. Am J Clin Nutr. 2007;86:843S–57S.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  15. Djavan B, Waldert M, Seitz C, Marberger M. Insulin-like growth factors and prostate cancer. World J Urol. 2001;19:225–33.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  20. Grundy M, Scott M. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol. 1998;81:18B–25B.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  22. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.

    CAS  PubMed  Google Scholar 

  23. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  26. Gennigens C, Menetrier-Caux C, Droz J. Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol. 2006;58:124.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  31. Dupont J, Holzenberger M. Biology of insulin like growth factors in development. Birth Defects Res C Embryo Today. 2003;69:257–71.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  33. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007;6:1–12.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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. LeRoith D, Roberts CT. The insulin-like growth factor system and cancer. Cancer Lett. 2003;195:127–37.

    CAS  PubMed  Google Scholar 

  38. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocrine Rev. 1999;20:761–87.

    CAS  Google Scholar 

  39. Baxter RC. Insulin-like growth factor binding proteins in the human circulation: a review. Horm Res Paediatr. 1994;42:140–4.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  63. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114:63–70.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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. Levitzki A, Mishani E. Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem. 2006;75:93–109.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  115. Kontermann RE. Recombinant bispecific antibodies for cancer therapy. Acta Pharmacol Sinica. 2005;26:1–9.

    CAS  Google Scholar 

  116. Deyev SM, Lebedenko EN. Multivalency: the hallmark of antibodies used for optimization of tumor targeting by design. BioEssays. 2008;30:904–18.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

  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. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

  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.

    CAS  PubMed  Google Scholar 

  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.

  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.

    PubMed  Google Scholar 

  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.

  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.

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Centre for Biosciences, School of Basic and Applied Science, Central University of Punjab, Bathinda, 151001, Punjab, India

    Pushpendra Singh & Felix Bast

  2. Centre for Chemical and Pharmaceutical Sciences, School of Basic and Applied Science, Central University of Punjab, Bathinda, 151001, Punjab, India

    Jimi Marin Alex

Authors
  1. Pushpendra Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jimi Marin Alex
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felix Bast
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felix Bast.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, P., Alex, J.M. & Bast, F. Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol 31, 805 (2014). https://doi.org/10.1007/s12032-013-0805-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0805-3

Keywords

Search

Navigation