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The Insulin-Like Growth Factor Pathway in Lung Cancer

      Abstract

      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.

      Key Words

      The insulin-like growth factor (IGF) pathway involves elements of endocrine, paracrine, and autocrine control in regulating fetal development, growth, and metabolism.
      • Clemmons DR
      Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer.
      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.
      • Clemmons DR
      Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer.
      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.
      • Chao W
      • D'Amore PA
      IGF2: epigenetic regulation and role in development and disease.
      IGF-1 is particularly important in somatic growth, with human mutations in IGF-1 producing severe growth retardation and mental impairment.
      • Denley A
      • Cosgrove LJ
      • Booker GW
      • Wallace JC
      • Forbes BE
      Molecular interactions of the IGF system.
      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.
      • Chao W
      • D'Amore PA
      IGF2: epigenetic regulation and role in development and disease.
      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.
      • Brown J
      • Delaine C
      • Zaccheo OJ
      • et al.
      Structure and functional analysis of the IGF-II/IGF2R interaction.
      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.
      • Clemmons DR
      Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer.
      • 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.
      Figure thumbnail gr1
      FIGURE 1Schematic representation of the IGF axis at the level of a peripheral tissue. Three different ligands (insulin, IGF-1, IGF-2) affected by upstream elements of hormonal control (prediminatly IGF-1) and imprinting (IGF-2), six different binding proteins, three different receptors, and a range of intracellular substrates and docking proteins influence intracellular signaling. The avidity of the different ligands for the different receptor combinations are shown in the embedded table. Activity in the pathway is also influenced by pTEN inhibition of the PI3K pathway, and p53-mediated receptor down-regulation, and therefore mutations in either/both genes may influence a tumor's dependence on the pathway.
      IGF-1R may also form hybrid multimeric receptors with other membrane receptors, for example, the epidermal growth factor receptor.
      • 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.
      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.
      • Yee D
      Targeting insulin-like growth factor pathways.
      • 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.
      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.
      • Hofmann F
      • Garcia-Echeverria C
      Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer.
      • 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.
      • 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.
      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.
      • 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.
      • 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.
      Similarly, IGFBP3 promoter methylation in tumor cells has been linked to decreased survival in stage I NSCLC patients.
      • 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.
      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.
      • Rudd MF
      • Webb EL
      • Matakidou A
      • et al.
      Variants in the GH-IGF axis confer susceptibility to lung cancer.
      Preclinically, IGF-1R activation acts as a cofactor for malignant transformation by a number of different stimuli.
      • Hartog H
      • Wesseling J
      • Boezen HM
      • van der Graaf WT
      The insulin-like growth factor 1 receptor in cancer: old focus, new future.
      Transgenic mice engineered to express constitutively active IGF-1R develop malignant tumors, including salivary and mammary adenocarcinomas.
      • Carboni JM
      • Lee AV
      • Hadsell DL
      • et al.
      Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor.
      Nearly 70% of transgenic mice over-expressing IGF-2 develop lung adenocarcinomas by 18 months of age.
      • Moorehead RA
      • Sanchez OH
      • Baldwin RM
      • Khokha R
      Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma.

      DEVELOPMENT OF IGF-1R INHIBITORS IN LUNG CANCER

      There are several strategies being explored to disrupt IGF pathway signaling in cancers (Figure 2).
      • Ryan PD
      • Goss PE
      The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer.
      • Sachdev D
      • Yee D
      Disrupting insulin-like growth factor signaling as a potential cancer therapy.
      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.
      • 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.
      In contrast, the small molecule inhibitors seem to reduce signaling without requiring receptor internalization.
      • 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.
      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.
      • Vaira V
      • Lee CW
      • Goel HL
      • Bosari S
      • Languino LR
      • Altieri DC
      Regulation of survivin expression by IGF-1/mTOR signaling.
      • Wendel HG
      • De Stanchina E
      • Fridman JS
      • et al.
      Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.
      Results of studies on cell lines and xenografts suggest synergistic activity of IGF-1R inhibitors with a variety of cytotoxic agents.
      • 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.
      • 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.
      • 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.
      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.
      • 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.
      • 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.
      IGF-1R activation is also involved in protection from ionizing radiation, and IGF-1R inhibitors increase radiation sensitivity of NSCLC cell lines.
      • Allen GW
      • Saba C
      • Armstrong EA
      • et al.
      Insulin-like growth factor-I receptor signaling blockade combined with radiation.
      • 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.
      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.
      • 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.
      • 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).

      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.

      • 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.
      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.

      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.

      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.
      • 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).
      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.
      Figure thumbnail gr2
      FIGURE 2Potential therapeutic strategies for reducing IGF pathway signaling. The dominant strategies currently being explored in the clinic are the monoclonal antibodies directed against the extracellular domain of the receptor, and small molecule inhibitors of the IGF-1R tyrosine kinase domain.

      CONCLUSIONS

      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.

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