Journal of Thoracic Oncology:
Pathway of the Month
The Insulin-Like Growth Factor Pathway in Lung Cancer
Dziadziuszko, Rafal MD, PhD*; Camidge, D Ross MD, PhD†; Hirsch, Fred R. MD, PhD†‡
*Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; †Division of Medical Oncology and ‡Pathology, University of Colorado Cancer Center, Aurora, Colorado.
Disclosure: Rafal Dziadziuszko served as a consultant for Roche. D. Ross Gamidge has no relevant disclosure to declare. Fred R. Hirsch served as a consultant for AstraZeneca, Roche, Genentech, Merck-Serono, Pfizer, Boehringer/Ingelheim, BMS/lmclone, Vent and Diagnostics and received research support from AstraZeneca, OSI Pharmaceuticals, Merck-Serono, Syndax, Genmab and Sanofi-Aventis.
Address for correspondence: Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center, P.O. Box 6511, Mail Stop 8117, Aurora, CO 80045. E-mail: Fred.Hirsch@UCHSC.edu
The insulin-like growth factor (IGF) pathway is involved in the normal control of fetal development, tissue growth, and metabolism. Two distinct ligands (insulin-like growth factor-1 [IGF-1] and IGF-2) plus insulin, and two receptors (insulin-like growth factor receptor-1 [IGF-1R] and the insulin receptor) capable of both homo- and heteropolymerization mediate the actions of this pathway. Cellular functions of IGF-regulated signaling are influenced by the expression of a variety of receptor docking proteins, including four different insulin receptor substrate proteins. Downstream signaling is primarily through the phosphatidylinositol-3 kinase-Akt pathway and the mitogen-activated protein kinase pathway, resulting in increased cell proliferation and apoptosis inhibition. Ligand-driven activation is influenced by upstream endocrine factors (particularly for IGF-1), imprinting (for IGF-2), by multiple circulating and tissue-based IGF-binding proteins/proteases, and by the expression of the IGF-2 clearance receptor (IGF-2R). Deregulation of IGF signaling has been described in several cancer types, including both small cell and non-small cell lung cancer. A number of IGF receptor inhibitors, including monoclonal antibodies and small molecule inhibitors are currently undergoing testing in clinical trials as both monotherapy, and in combination with chemotherapy, or with other targeted agents. Preliminary results from a randomized phase II trial of an anti-IGF-1R monoclonal antibody in combination with carboplatin/paclitaxel already suggest a potential efficacy benefit from targeting this pathway in the first line advanced non-small cell lung cancer setting.
The insulin-like growth factor (IGF) pathway involves elements of endocrine, paracrine, and autocrine control in regulating fetal development, growth, and metabolism.1 Growth hormone stimulates production of insulin-like growth factor-1 (IGF-1) in the liver and peripheral tissues. IGF-1 is also released locally in response to damage, either directly or through the action of other factors associated with tissue responses to damage, including epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor.1
The related IGF-2 is present in the circulation at two to three times the levels of IGF-1, and is also produced in the liver and peripheral tissues, but its production is mostly controlled through imprinting-mediated gene dosage regulation.2 IGF-1 is particularly important in somatic growth, with human mutations in IGF-1 producing severe growth retardation and mental impairment.3 The role of IGF-2 seems to vary between species. In rodents, IGF-2 has a minor role in embryonic growth development but little role in adult animals, in contrast to in humans, where it is the predominant IGF in adults.2 Both ligands mediate their effects through activation of the insulin-like growth factor receptor-1 (IGF-1R), which is highly homologous to the insulin receptor (IR). Each ligand also has some activity against IR splice variants (IR-A and IR-B) and/or hybrids of the two receptors (Figure 1). The IGF-1R has a 15- to 20-fold higher affinity for IGF-1 than IGF-2, consistent with its name. Nevertheless, the greater binding potential of IGF-2 across different receptors may give it a broader range of biologic functions than IGF-1. The IGF-2R has no known signal transduction properties and serves as a clearance receptor for IGF-2.4 The concentration of free ligands and their exposure kinetics are tightly regulated in the circulation and/or periphery by a range of high-affinity binding proteins (IGFBP1–6) and their proteases. All the IGFBPs have a greater affinity than the IGF-receptors for their ligands. In general, it is difficult to ascribe simple roles to the IGFBPs as their effects, modulating the kinetics of free IGF exposure, could in theory, both increase and decrease IGF-related signaling, depending on the time frame considered. IGFBP3 is the dominant circulating binding partner for both IGFs, accounting for 70 to 80% of their blood levels.1,5
IGF-1R may also form hybrid multimeric receptors with other membrane receptors, for example, the epidermal growth factor receptor.6 After ligand binding, conformational changes in the IGF-1R result in activation of its tyrosine kinase domain, phosphorylation of insulin receptor substrate proteins (IRS 1–4), and recruitment of a range of docking proteins The expression of different IRS molecules may be tissue specific, and may also differentiate various aspects of the malignant phenotype associated with this pathway, for example, IRS1 has been associated with proliferation, whereas IRS2 has been associated with metastatic behavior.7,8 Downstream of the receptors the mitogen-activated kinase and phosphatidylinositol-3 kinase-Akt (PI3K-Akt) pathways become broadly activated, leading to cell proliferation and inhibition of programmed cell death.
IGF PATHWAY AND LUNG CANCER
Multiple lines of evidence suggest involvement of the IGF pathway across a range of malignancies, including both non-small cell lung cancer (NSCLC) and small cell lung cancer.9–11 Elevated plasma levels of IGF-1 have been associated with an increased risk of lung cancer, and high plasma levels of IGFBP3 associated with a reduced risk.11,12 Similarly, IGFBP3 promoter methylation in tumor cells has been linked to decreased survival in stage I NSCLC patients.13 A large case-control study of Whites identified 64 single nucleotide polymorphisms associated with lung cancer risk, of which 11 were related to the growth hormone-insulin-like growth factor axis.14 Preclinically, IGF-1R activation acts as a cofactor for malignant transformation by a number of different stimuli.15 Transgenic mice engineered to express constitutively active IGF-1R develop malignant tumors, including salivary and mammary adenocarcinomas.16 Nearly 70% of transgenic mice over-expressing IGF-2 develop lung adenocarcinomas by 18 months of age.17
DEVELOPMENT OF IGF-1R INHIBITORS IN LUNG CANCER
There are several strategies being explored to disrupt IGF pathway signaling in cancers (Figure 2).18,19 The two dominant strategies currently being explored are monoclonal antibodies directed against the extracellular domain of the IGF-1R, and small molecule inhibitors of its intracellular kinase domain. The monoclonal antibodies are further advanced in clinical development at present and seem to act primarily through down-regulation of the IGF-1R.20 In contrast, the small molecule inhibitors seem to reduce signaling without requiring receptor internalization.21 Because of direct effects on IRs, and/or complementary signaling between the pathways, hyperglycemia (potentially controllable with oral agents such as metformin) has already been noted and is anticipated to be a class-specific toxicity. IGF-1R activation provides a potential mechanism of cell protection to cytotoxic chemotherapeutics through increased downstream signaling through the prosurvival PI3K-Akt pathway.22,23 Results of studies on cell lines and xenografts suggest synergistic activity of IGF-1R inhibitors with a variety of cytotoxic agents.24–26 Prolonged treatment of NSCLC cell lines with low concentrations of erlotinib or gefitinib resulted in acquired resistance mediated by activated IGF-1R with IGF-1R/epidermal growth factor receptor heterodimer formation leading to up-regulation of survivin expression.6,27 IGF-1R activation is also involved in protection from ionizing radiation, and IGF-1R inhibitors increase radiation sensitivity of NSCLC cell lines.28,29 These findings support the clinical testing of combinations of IGF-1R inhibitors with both traditional anticancer therapies (cytotoxics, radiotherapy) and targeted agents in lung cancer. Phase I monotherapy study results reported for the monoclonal antibodies CP-751,871, R1507, AMG 479, and IMC-A12 have shown little in the way of toxicities, apart from some hyperglycemia and, for some of the antibodies, thrombocytopenia.30–33 There have been hints of single agent activity across several different cancer types in these all-comers studies, but noted dramatic single agent activity in Ewing sarcoma patients, fast-tracking a range of subsequent sarcoma-specific phase II studies.32 To date, in lung cancer, preliminary phase II results of only one anti-IGF-1R agent have been reported. In a randomized first-line advanced NSCLC phase II study of paclitaxel and carboplatin plus/minus CP751,871, 46% of patients in the experimental arm achieved objective responses (22/48 patients) versus 32% (8/25 patients) in the control arm.31 An unplanned subgroup analysis by histology has suggested a greater benefit in patients with squamous histology within this trial, but the results of additional patient numbers, including planned enrichment for those with squamous histology, are awaited.
The IGF pathway is implicated in the induction and maintenance of a range of different malignancies. Its activity is influenced by a range of different ligands, upstream hormonal regulation, imprinting, binding protein and protease expression, signaling and clearance receptor expression and hybridization, and intracellular substrate expression. Clinical data already show a favorable toxicity profile and some monotherapy activity signals for several anti-IGF-1R monoclonal antibodies, whereas little data on the tolerability or efficacy of the small molecule inhibitors of the IGF-1R are currently available. Early efficacy signals from a phase II study of CP-751,871 in combination with carboplatin/paclitaxel in advanced NSCLC are promising, however, final reports of this trial are awaited and several other trials of anti-IGF-1R antibodies in combination studies in lung cancer are ongoing. The challenge will inevitably be how to optimally select patients to treat with IGF-1R inhibitors based on the molecular characteristics of their tumors, and several correlative studies looking across the range of factors known to influence activating within this pathway are currently underway in association with these clinical trials.
1. Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 2007;6:821–833.
2. Chao W, D’Amore PA. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev 2008;19:111–120.
3. Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev 2005;16:421–439.
4. Brown J, Delaine C, Zaccheo OJ, et al. Structure and functional analysis of the IGF-II/IGF2R interaction. EMBO J 2008;27:265–276.
5. Oh SH, Lee OH, Schroeder CP, et al. Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition. Mol Cancer Ther 2006;5:2685–2695.
6. Morgillo F, Woo JK, Kim ES, Hong WK, Lee HY. Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res 2006;66:10100–10111.
7. Yee D. Targeting insulin-like growth factor pathways. Br J Cancer 2006;94:465–468.
8. Zhang X, Kamaraju S, Hakuno F, et al. Motility response to insulin-like growth factor-I (IGF-I) in MCF-7 cells is associated with IRS-2 activation and integrin expression. Breast Cancer Res Treat 2004;83:161–170.
9. Hofmann F, Garcia-Echeverria C. Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drug Discov Today 2005;10:1041–1047.
10. 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 Clin Pract Oncol 2007;4:591–602.
11. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999;91:151–156.
12. London SJ, Yuan JM, Travlos GS, et al. Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China. J Natl Cancer Inst 2002;94:749–754.
13. Chang YS, Wang L, Liu D, et al. Correlation between insulin-like growth factor-binding protein-3 promoter methylation and prognosis of patients with stage I non-small cell lung cancer. Clin Cancer Res 2002;8:3669–3675.
14. Rudd MF, Webb EL, Matakidou A, et al. Variants in the GH-IGF axis confer susceptibility to lung cancer. Genome Res 2006;16:693–701.
15. 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;43:1895–1904.
16. Carboni JM, Lee AV, Hadsell DL, et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res 2005;65:3781–3787.
17. Moorehead RA, Sanchez OH, Baldwin RM, Khokha R. Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma. Oncogene 2003;22:853–857.
18. Ryan PD, Goss PE. The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer. Oncologist 2008;13:16–24.
19. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 2007;6:1–12.
20. Cohen BD, Baker DA, Soderstrom C, et al. 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 2005;11:2063–2073.
21. Ji QS, Mulvihill MJ, Rosenfeld-Franklin M, et al. A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo. Mol Cancer Ther 2007;6:2158–2167.
22. Vaira V, Lee CW, Goel HL, Bosari S, Languino LR, Altieri DC. Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 2007;26:2678–2684.
23. Wendel HG, De Stanchina E, Fridman JS, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004;428:332–337.
24. Goetsch L, Gonzalez A, Leger O, et al. 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 2005;113:316–328.
25. 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;13:5549s–5555s.
26. Warshamana-Greene GS, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal GW. The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 2005;11:1563–1571.
27. Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 2007;13:2795–2803.
28. Allen GW, Saba C, Armstrong EA, et al. Insulin-like growth factor-I receptor signaling blockade combined with radiation. Cancer Res 2007;67:1155–1162.
29. Cosaceanu D, Budiu RA, Carapancea M, Castro J, Lewensohn R, Dricu A. Ionizing radiation activates IGF-1R triggering a cytoprotective signaling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase-dependent mechanism. Oncogene 2007;26:2423–2434.
30. Haluska P, Shaw HM, Batzel GN, et al. Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res 2007;13:5834–5840.
31. Karp DD, Paz-Ares LG, Blakely LJ, et al. Efficacy of the anti-insulin like growth factor I receptor (IGF-IR) antibody CP-751871 in combination with paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). J Clin Oncol. ASCO Annu Meet Proc Part I 2007;25(18S):7506.
32. Leong S, Gore L, Benjamin R, et al. A phase I study of R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist given weekly in patients with advanced solid tumors. In Proceedings of AACR-NCI-EORTC International Conference “Molecular Tergets and Cancer Therapeutics”, San Francisco, Oct. 22–26, 2007:A78.
33. Tolcher AW, Rothenberg ML, Rodon J, et al. A phase I pharmacokinetic and pharmacodynamic study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R), in advanced solid tumors. J Clin Oncol. ASCO Annu Meet Proc Part I 2007;25(18S):3002.
This article has been cited 15 time(s).
Plos OneTargeting Non-Small Cell Lung Cancer Cells by Dual Inhibition of the Insulin Receptor and the Insulin-Like Growth Factor-1 ReceptorPlos One
Biopreservation and BiobankingIn Vitro Assessment of Apoptosis and Necrosis Following Cold Storage in a Human Airway Cell ModelBiopreservation and Biobanking
Molecular and Cellular BiochemistryLentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits growth, reduces invasion, and enhances radiosensitivity in human osteosarcoma cellsMolecular and Cellular Biochemistry
Insulin-like Growth Factor-1 Receptor (IGF-1R) in Primary and Metastatic Undifferentiated Carcinoma of the Head and Neck: A Possible Target of Immunotherapy
Anticancer Research, 30(5):
Expert Opinion on Investigational DrugsThe potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancerExpert Opinion on Investigational Drugs
Steroid Enzymes and CancerTargeting Aromatase and Estrogen Signaling in Human Non-Small Cell Lung CancerSteroid Enzymes and Cancer
Translational ResearchNovel insulin-like growth factor-methotrexate covalent conjugate inhibits tumor growth in vivo at lower dosage than methotrexate aloneTranslational Research
OncogeneThe IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancerOncogene
Expert Opinion on Therapeutic PatentsAdvances in preclinical small molecules for the treatment of NSCLCExpert Opinion on Therapeutic Patents
Clinical Lung CancerDevelopment of the Monoclonal Antibody Figitumumab, Targeting the Insulin-like Growth Factor-1 Receptor, for the Treatment of Patients with Non-Small-Cell Lung CancerClinical Lung Cancer
Journal of Clinical OncologyInsulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non-Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA ExpressionJournal of Clinical Oncology
Cancer ResearchInhibition of Cholinergic Signaling Causes Apoptosis in Human Bronchioalveolar CarcinomaCancer Research
Cancer Chemotherapy and PharmacologyReceptor tyrosine kinase alterations and therapeutic opportunities in squamous cell carcinoma of the lungCancer Chemotherapy and Pharmacology
Insulin-like growth factor; lung cancer
© 2008International Association for the Study of Lung Cancer
Highlight selected keywords in the article text.