Novel Targets for the Treatment of Pancreatic Cancer I: Insulin-like Growth Factor Receptor

  • Chris H. Takimoto
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

The field of oncology drug development is undergoing radical change. The development of molecular targeted therapies is altering previously established paradigms for drug discovery. Instead of simplistic searches for toxic cellular poisons, modern drug discovery is now a sophisticated, rationally designed, scientifically driven process employing high throughput, mechanism-based screening strategies. Fueling this change is the rapid growth in our understanding of cancer at the molecular level. Advances in biomedical research, such as the sequencing of the human genome, are accelerating this process. Unlike classic chemotherapy, the newer targeted treatments for cancer specifically exploit fundamental differences between normal and malignant cells. A prime example is the Bcr-Abl fusion protein, an abnormal constitutively activated tyrosine kinase that is responsible for the development of chronic myelogenous leukemia (CML) (1). A rationally designed and thoughtfully implemented effort to discover specific inhibitors of this abnormal kinase ultimately led to the discovery of imatinib (Gleevec™). This small molecule kinase inhibitor subsequently demonstrated impressive anticancer activity in phase I clinical trials in CML patients. Surprisingly, it also demonstrated impressive activity in gastrointestinal stromal cell tumors (GIST), largely because of its ability to inhibit the c-Kit kinase, another constitutively active signaling protein found in GIST. Thus, our growing understanding of the molecular basis for cancer is changing our approach to drug discovery across the globe.

Currently, most ongoing clinical research on targeted therapies for this disease is focusing on the VEGF and EGFR signaling pathways using agents such as bevacizumab (Avastin™) or cetuximab (Erbitux™), often in combination with established chemotherapeutic agents. These strategies are largely based upon the success of this approach in the treatment of other gastrointestinal malignancies, such as colorectal cancer. This and the next chapter attempt to anticipate further into the future by focusing on some novel targets for pancreatic cancer that are just entering into clinical development. These include targeting the insulin-like growth factor receptor and the Hedgehog cancer stem cell signaling pathways. At this relatively early stage of clinical development, it is impossible to predict precisely how successful these specific strategies will be. It is both exciting and exhilarating to hypothesize that these highly promising areas of scientific research may provide the foundation for tomorrow’s great therapeutic advances in the treatment of this devastating disease.


Pancreatic Cancer Insulin Receptor Pancreatic Tumor Human Pancreatic Cancer Pancreatic Cancer Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Druker BJ, 2004, Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91:1–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Burris HA, 3rd, Moore MJ, Andersen J, 1997, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413.PubMedGoogle Scholar
  3. 3. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007.Google Scholar
  4. 4.
    Giovannetti E, Mey V, Nannizzi S, 2006, Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer. Mol Cancer Ther 5:1387–1395.CrossRefPubMedGoogle Scholar
  5. 5.
    Rane SG, Lee JH, Lin HM, 2006, Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease. Cytokine Growth Factor Rev 17:107–119.CrossRefPubMedGoogle Scholar
  6. 6.
    Di Renzo MF, Poulsom R, Olivero M, 1995, Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res 55:1129–1138.PubMedGoogle Scholar
  7. 7.
    Butler AA, Yakar S, Gewolb IH, 1998, Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. Comp Biochem Physiol B Biochem Mol Biol 121:19–26.CrossRefPubMedGoogle Scholar
  8. 8.
    Surmacz E. 2003, Growth factor receptors as therapeutic targets: strategies to inhibit the insu-lin-like growth factor I receptor. Oncogene 22: 6589–6597.CrossRefPubMedGoogle Scholar
  9. 9.
    Pollak MN, Schernhammer ES, Hankinson SE, 2004, Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518.CrossRefPubMedGoogle Scholar
  10. 10.
    Lin Y, Tamakoshi A, Kikuchi S, 2004, Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death. Int J Cancer 110:584–588.CrossRefPubMedGoogle Scholar
  11. 11.
    Hofmann F, Garcia-Echeverria C. 2005, Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drug Discov Today 10:1041–1047.CrossRefPubMedGoogle Scholar
  12. 12.
    Miller BS, Yee D, 2005, Type I insulin-like growth factor receptor as a therapeutic target in cancer. Cancer Res 65:10123–10127.CrossRefPubMedGoogle Scholar
  13. 13.
    Larsson O, Girnita A, Girnita L, 2005, Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer 92:2097–2101.CrossRefPubMedGoogle Scholar
  14. 14.
    Durai R, Yang W, Gupta S, 2005, The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge. Int J Colorectal Dis 20: 203–220.CrossRefPubMedGoogle Scholar
  15. 15.
    Sachdev D, Yee D. 2007, Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6:1–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Cui H, Cruz-Correa M, Giardiello FM, 2003, Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299:1753–1755.CrossRefPubMedGoogle Scholar
  17. 17.
    Ouban A, Muraca P, Yeatman T, 2003, Expression and distribution of insulin-like growth fac-tor-1 receptor in human carcinomas. Hum Pathol 34: 803–808.CrossRefPubMedGoogle Scholar
  18. 18.
    Weber MM, Fottner C, Liu SB, 2002, Overexpression of the insulin-like growth factor I recep-tor in human colon carcinomas. Cancer 95:2086–2095.CrossRefPubMedGoogle Scholar
  19. 19.
    Happerfield LC, Miles DW, Barnes DM, 1997, The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue. J Pathol 183:412–417.CrossRefPubMedGoogle Scholar
  20. 20.
    Hellawell GO, Turner GD, Davies DR, 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 62:2942–2950.PubMedGoogle Scholar
  21. 21.
    Cappuzzo F, Toschi L, Tallini G, 2006, I nsulin-like growth factor receptor 1 (IGFR-1) is sig-nificantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib. Ann Oncol 17:1120–1127.CrossRefPubMedGoogle Scholar
  22. 22.
    Shigematsu K, Kataoka Y, Kamio T, 1990, Partial characterization of insulin-like growth fac-tor I in primary human lung cancers using immunohistochemical and receptor autoradio-graphic techniques. Cancer Res 50:2481–2484.PubMedGoogle Scholar
  23. 23.
    Xie Y, Skytting B, Nilsson G, 1999, Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype. Cancer Res 59: 3588–3591.PubMedGoogle Scholar
  24. 24.
    Bergmann U, Funatomi H, Yokoyama M, 1995, Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res 55: 2007–2011.PubMedGoogle Scholar
  25. 25.
    Baciuchka M, Remacle-Bonnet M, Garrouste F, 1998, Insulin-like growth factor (IGF)-bind-ing protein-3 (IGFBP-3) proteolysis in patients with colorectal cancer: possible association with the metastatic potential of the tumor. Int J Cancer 79:460–467.CrossRefPubMedGoogle Scholar
  26. 26.
    Meyts P, De Wallach B, Christoffersen CT, 1994, The insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction. Horm Res 42:152–169.CrossRefPubMedGoogle Scholar
  27. 27.
    Nair PN, Armond DT, De Adamo ML, 2001, Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2. Oncogene 20:8203–8214.CrossRefPubMedGoogle Scholar
  28. 28.
    Woods KA, Camacho-Hubner C, Savage MO, 1996, Intrauterine growth retardation and post-natal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335:1363–1367.CrossRefPubMedGoogle Scholar
  29. 29.
    Laron Z, Klinger B, Erster B, 1988, Effect of acute administration of insulin-like growth factor I in patients with Laron-type dwarfism. Lancet 2: 1170–1172.CrossRefPubMedGoogle Scholar
  30. 30.
    Abuzzahab MJ, Schneider A, Goddard A, 2003, IGF-I receptor mutations resulting in intrau-terine and postnatal growth retardation. N Engl J Med 349:2211–2222.CrossRefPubMedGoogle Scholar
  31. 31.
    Liu JP, Baker J, Perkins AS, 1993, Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75: 59–72.PubMedGoogle Scholar
  32. 32.
    Kaleko M, Rutter WJ, Miller AD. 1990, Overexpression of the human insulinlike growth fac-tor I receptor promotes ligand-dependent neoplastic transformation. Mol Cell Biol 10:464–473.PubMedGoogle Scholar
  33. 33.
    Wu Y, Yakar S, Zhao L, 2002, Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 62:1030–1035.PubMedGoogle Scholar
  34. 34.
    Sachdev D, Hartell JS, Lee AV, 2004, A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem 279:5017–5024.CrossRefPubMedGoogle Scholar
  35. 35.
    Yu H, Rohan T. 2000, Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92:1472–1489.CrossRefPubMedGoogle Scholar
  36. 36.
    Ueda S, Hatsuse K, Tsuda H, 2006, Potential crosstalk between insulin-like growth factor receptor type 1 and epidermal growth factor receptor in progression and metastasis of pancre-atic cancer. Mod Pathol 19:788–796.PubMedGoogle Scholar
  37. 37.
    Lu Y, Zi X, Zhao Y, 2001, I nsulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857.CrossRefPubMedGoogle Scholar
  38. 38.
    Stoeltzing O, Liu W, Reinmuth N, 2003, Regulation of hypoxia-inducible factor-1alpha, vas-cular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am J Pathol 163:1001–1011.PubMedGoogle Scholar
  39. 39.
    Zeng H, Datta K, Neid M, 2003, Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line. Biochem Biophys Res Commun 302:46–55.CrossRefPubMedGoogle Scholar
  40. 40.
    Min Y, Adachi Y, Yamamoto H, 2003, Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer. Cancer Res 63:6432–6441.PubMedGoogle Scholar
  41. 41.
    Goya M, Miyamoto S, Nagai K, 2004, 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 64:6252–6258.CrossRefPubMedGoogle Scholar
  42. 42.
    Yee D, Jackson JG, Kozelsky TW, 1994, Insulin-like growth factor binding protein 1 expres-sion inhibits insulin-like growth factor I action in MCF-7 breast cancer cells. Cell Growth Differ 5:73–77.PubMedGoogle Scholar
  43. 43.
    den Berg CL, Van Cox GN, Stroh CA, 1997, Polyethylene glycol conjugated insulin-like growth factor binding protein-1 (IGFBP-1) inhibits growth of breast cancer in athymic mice. Eur J Cancer 33:1108–1113.CrossRefGoogle Scholar
  44. 44.
    Lu D, Zhang H, Koo H, 2005, A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity. J Biol Chem 280: 19665–19672.CrossRefPubMedGoogle Scholar
  45. 45.
    Burtrum D, Zhu Z, Lu D, 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 63:8912–8921.PubMedGoogle Scholar
  46. 46. Higano CS, Yu Y, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. 2007 Prostate Cancer Symposium 2007, 269.Google Scholar
  47. 47.
    Maloney EK, McLaughlin JL, Dagdigian NE, 2003, An anti-insulin-like growth factor I recep-tor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res 63:5073–5083.PubMedGoogle Scholar
  48. 48.
    Cohen BD, Baker DA, Soderstrom C, 2005, Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 11:2063–2073.CrossRefPubMedGoogle Scholar
  49. 49.
    Goetsch L, Gonzalez A, Leger O, 2005, A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer 113:316–328.CrossRefPubMedGoogle Scholar
  50. 50.
    Garcia-Echeverria C, Pearson MA, Marti A, 2004, In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5:231–239.CrossRefPubMedGoogle Scholar
  51. 51.
    Warshamana-Greene GS, Litz J, Buchdunger E, 2005, The insulin-like growth factor-I recep-tor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 11:1563–1571.CrossRefPubMedGoogle Scholar
  52. 52.
    Wittman M, Carboni J, Attar R, 2005, Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo anti-tumor activity. J Med Chem 48:5639–5643.CrossRefPubMedGoogle Scholar
  53. 53.
    Haluska P, Carboni JM, Loegering DA, 2006, In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res 66:362–371.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Chris H. Takimoto
    • 1
    • 2
  1. 1.University of Texas Health Science CenterSan Antonio
  2. 2.Accelerated Research TherapeuticsSan AntonioUSA

Personalised recommendations