Targeting the insulin growth factor receptor 1.

The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation. Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozygosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool.

[1]  Stevan R. Hubbard,et al.  Structure and autoregulation of the insulin-like growth factor 1 receptor kinase , 2001, Nature Structural Biology.

[2]  Zora Modrusan,et al.  Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma , 2007, Proceedings of the National Academy of Sciences.

[3]  Gang Meng,et al.  Hypomethylation of the P3 promoter is associated with up-regulation of IGF2 expression in human osteosarcoma. , 2009, Human pathology.

[4]  Wenhan He,et al.  Hypomethylated and hypermethylated profiles of H19DMR are associated with the aberrant imprinting of IGF2 and H19 in human hepatocellular carcinoma. , 2008, Genomics.

[5]  A. Gualberto,et al.  Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions , 2009, Oncogene.

[6]  C. Scott,et al.  The role of the M6P/IGF-II receptor in cancer: tumor suppression or garbage disposal? , 2004, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[7]  W. Walsh,et al.  IGF1R-Targeted Therapy and Its Enhancement of Doxorubicin Chemosensitivity in Human Osteosarcoma Cell Lines , 2011, Cancer investigation.

[8]  S. Zhan,et al.  Loss of imprinting of IGF2 in Ewing's sarcoma. , 1995, Oncogene.

[9]  L. Helman,et al.  Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism , 2007, Oncogene.

[10]  F. V. Schaik,et al.  Sequence of cDNA encoding human insulin-like growth factor I precursor , 1983, Nature.

[11]  D. Reinke,et al.  R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  O. Delattre,et al.  EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3 , 2004, Molecular and Cellular Biology.

[13]  J. Castro,et al.  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 , 2007, Oncogene.

[14]  J. Gee,et al.  Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer , 2000, British Journal of Cancer.

[15]  A. Gualberto,et al.  Clinical development of inhibitors of the insulin-like growth factor receptor in oncology. , 2009, Current drug targets.

[16]  Ling Xia,et al.  Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. , 2009, Cancer research.

[17]  H. Modjtahedi,et al.  Coexpression of the IGF-IR, EGFR and HER-2 is common in colorectal cancer patients. , 2006, International journal of oncology.

[18]  A. Astolfi,et al.  The emerging role of insulin-like growth factor 1 receptor (IGF1r) in gastrointestinal stromal tumors (GISTs) , 2010, Journal of Translational Medicine.

[19]  A. Feinberg,et al.  Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk , 2003, Science.

[20]  J. Zalcberg,et al.  Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line , 1999, British Journal of Cancer.

[21]  Meir J. Stampfer,et al.  Plasma Insulin-Like Growth Factor-I and Prostate Cancer Risk: A Prospective Study , 1998 .

[22]  T. Pandita,et al.  Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. , 2004, Endocrinology.

[23]  R. Weindruch,et al.  Aging and cancer-related loss of insulin-like growth factor 2 imprinting in the mouse and human prostate. , 2008, Cancer research.

[24]  E. Ghigo,et al.  Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients , 2012, Diabetes, obesity & metabolism.

[25]  R H Hruban,et al.  Gene expression profiles in normal and cancer cells. , 1997, Science.

[26]  K. Kang,et al.  Induction of Glutathione Transferase in Insulin-Like Growth Factor Type I Receptor-Overexpressed Hepatoma Cells , 2007, Molecular Pharmacology.

[27]  P. Sorensen,et al.  The Insulin-Like Growth Factor I Receptor Is Required for Akt Activation and Suppression of Anoikis in Cells Transformed by the ETV6-NTRK3 Chimeric Tyrosine Kinase , 2006, Molecular and Cellular Biology.

[28]  H. Orskov,et al.  Free insulin-like growth factors in human obesity. , 1995, Metabolism: clinical and experimental.

[29]  A. Belfiore.  The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. , 2007, Current pharmaceutical design.

[30]  R. Nicholson,et al.  Prospects for combining hormonal and nonhormonal growth factor inhibition. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[31]  M. Schubert,et al.  The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. , 2009, Current Alzheimer research.

[32]  W. Oyen,et al.  ImmunoSPECT and ImmunoPET of IGF-1R Expression with the Radiolabeled Antibody R1507 in a Triple-Negative Breast Cancer Model , 2010, The Journal of Nuclear Medicine.

[33]  H. Werner,et al.  Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression , 1995, Molecular and cellular biology.

[34]  G. Booker,et al.  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. , 2004, Molecular endocrinology.

[35]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[36]  F. Hirsch,et al.  Increased Insulin-Like Growth Factor 1 Receptor Protein Expression and Gene Copy Number in Small Cell Lung Cancer , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[37]  A. Ashworth,et al.  A Distinct Spectrum of Copy Number Aberrations in Pediatric High-Grade Gliomas , 2010, Clinical Cancer Research.

[38]  D. Yee,et al.  Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. , 2008, The Journal of clinical investigation.

[39]  C. Roberts,et al.  The insulin-like growth factor system and cancer. , 2003, Cancer letters.

[40]  J. Riedemann,et al.  IGF1R signalling and its inhibition. , 2006, Endocrine-related cancer.

[41]  M. Rubini,et al.  Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Han You,et al.  Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. , 2006, Genes & development.

[43]  Cunming Duan,et al.  Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation. , 2010, General and comparative endocrinology.

[44]  Z. Gucev,et al.  Insulin-like Growth Factor Binding Protein 3 Mediates Retinoic Acid- and Transforming Growth Factor β2-induced Growth Inhibition in Human Breast Cancer Cells , 1996 .

[45]  T. Yeatman,et al.  Expression of insulin-like growth factor-1 receptor in human colorectal cancer. , 1999, Human pathology.

[46]  A. Tolcher,et al.  Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  S. Schuetze,et al.  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. , 2010, The Lancet. Oncology.

[48]  D. Beech,et al.  Insulin-like growth factor-I receptor antagonism results in increased cytotoxicity of breast cancer cells to doxorubicin and taxol. , 2001, Oncology reports.

[49]  S. Hankinson,et al.  Insulin-like growth factors and neoplasia , 2004, Nature Reviews Cancer.

[50]  Helen X. Chen,et al.  Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer , 2011, Clinical Cancer Research.

[51]  H. Masoudi,et al.  Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. , 2008, Cancer research.

[52]  S. Thomson,et al.  Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. , 2008, Cancer research.

[53]  P. Elizalde,et al.  Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insulin-like growth factor receptor in mammary tumor cells , 2001, Oncogene.

[54]  D. Leroith,et al.  The Insulin-like Growth Factor-I Receptor Is Required for EWS/FLI-1 Transformation of Fibroblasts* , 1997, The Journal of Biological Chemistry.

[55]  P. De Meyts.  Insulin and its receptor: structure, function and evolution. , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[56]  S. Brewster,et al.  Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer , 2005, Cancer Gene Therapy.

[57]  Y. Shiloh,et al.  Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase , 2001, Oncogene.

[58]  A. Klibanski,et al.  Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly. , 1995, The Journal of clinical endocrinology and metabolism.

[59]  A. Belfiore,et al.  Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer. , 1999, Biochimie.

[60]  M. Raderer,et al.  The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  D. Dunger,et al.  Pegvisomant: current and potential novel therapeutic applications , 2009, Expert opinion on biological therapy.

[62]  F. Hofmann,et al.  The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy , 2005, Clinical Cancer Research.

[63]  H. Fan,et al.  LOI of IGF2 is associated with esophageal cancer and linked to methylation status of IGF2 DMR. , 2006, Journal of experimental & clinical cancer research : CR.

[64]  R. Poulsom,et al.  Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. , 2002, Cancer research.

[65]  A. Feinberg,et al.  Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. , 2001, Journal of the National Cancer Institute.

[66]  J. Mendelsohn.  The epidermal growth factor receptor as a target for cancer therapy. , 2001, Endocrine-Related Cancer.

[67]  K. Ow,et al.  Expression of insulin-like growth factor mitogenic signals in adult soft-tissue sarcomas: significant correlation with malignant potential , 2004, Virchows Archiv.

[68]  F. Frasca,et al.  The role of insulin receptors and IGF-I receptors in cancer and other diseases , 2008, Archives of physiology and biochemistry.

[69]  Dirk Hadaschik,et al.  Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation. , 2007, The Biochemical journal.

[70]  H. Huynh,et al.  Antiproliferative action of vitamin D-related compounds and insulin-like growth factor-binding protein 5 accumulation. , 1997, Journal of the National Cancer Institute.

[71]  M. Waters,et al.  Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. , 2000, The Journal of clinical endocrinology and metabolism.

[72]  W. Tamborlane,et al.  Effect of Diabetes and its Control on Insulin-like Growth Factors in the Young Subject with Type I Diabetes , 1984, Diabetes.

[73]  D. Slamon,et al.  HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  D. Balzi,et al.  Metformin and Cancer Occurrence in Insulin-Treated Type 2 Diabetic Patients , 2010, Diabetes Care.

[75]  J. A. Scarlett,et al.  Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice. , 2001, Journal of neurosurgery.

[76]  Edward S. Kim,et al.  Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. , 2006, Cancer research.

[77]  Martine J Jager,et al.  Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. , 2002, Investigative ophthalmology & visual science.

[78]  Chun-Che Lin,et al.  Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation , 2011, Journal of gastroenterology and hepatology.

[79]  Jiye Yin,et al.  Expression Levels of Insulin-Like Growth Factor-1 and Multidrug Resistance-Associated Protein-1 Indicate Poor Prognosis in Patients with Gastric Cancer , 2009, Digestion.

[80]  W. Broaddus,et al.  Wilms’ tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression , 2011, Journal of Neuro-Oncology.

[81]  M. Thun,et al.  Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. , 2004, American journal of epidemiology.

[82]  Edward S. Kim,et al.  Implication of the Insulin-like Growth Factor-IR Pathway in the Resistance of Non–small Cell Lung Cancer Cells to Treatment with Gefitinib , 2007, Clinical Cancer Research.

[83]  M. Pollak,et al.  Estradiol and Antiestrogens Regulate a Growth Inhibitory Insulin-like Growth Factor Binding Protein 3 Autocrine Loop in Human Breast Cancer Cells (*) , 1996, The Journal of Biological Chemistry.

[84]  M. Pollak.  Insulin-like growth factor-related signaling and cancer development. , 2007, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[85]  J. Barretina,et al.  Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification , 2010, International journal of cancer.

[86]  Adrian V. Lee,et al.  The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. , 2008, Frontiers in bioscience : a journal and virtual library.

[87]  S. Velasco-Miguel,et al.  Induction of the growth inhibitor IGF-binding protein 3 by p53 , 1995, Nature.

[88]  J. McCubrey,et al.  Synergy between PI3K/Akt and Raf/MEK/ERK Pathways in IGF-1R Mediated Cell Cycle Progression and Prevention of Apoptosis in Hematopoietic Cells , 2004, Cell cycle.

[89]  P. Glazer,et al.  Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. , 1997, Cancer research.

[90]  A. Flyvbjerg,et al.  Growth hormone receptor antagonist administration inhibits growth of human colorectal carcinoma in nude mice. , 2004, Anticancer research.

[91]  B. Leyland-Jones,et al.  Recombinant human insulin-like growth factor-binding protein 3 inhibits tumor growth and targets the Akt pathway in lung and colon cancer models. , 2008, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[92]  L. Hennighausen,et al.  Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. , 2003, Cancer research.

[93]  P. Parren,et al.  Human IgG2 Antibodies against Epidermal Growth Factor Receptor Effectively Trigger Antibody-Dependent Cellular Cytotoxicity but, in Contrast to IgG1, Only by Cells of Myeloid Lineage , 2009, The Journal of Immunology.

[94]  T. Sørensen,et al.  Growth patterns and the risk of breast cancer in women. , 2004, The New England journal of medicine.

[95]  D. Carbone,et al.  Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts , 2005, Gut.

[96]  R. Nicholson,et al.  Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. , 2005, Endocrinology.

[97]  Shan-Chun Chen,et al.  Autocrine stimulation by insulin-like growth factor I is involved in the growth, tumorigenicity and chemoresistance of human esophageal carcinoma cells. , 2002, Journal of biomedical science.

[98]  Bin Wang,et al.  Lentivirus-mediated shRNA targeting insulin-like growth factor-1 receptor (IGF-1R) enhances chemosensitivity of osteosarcoma cells in vitro and in vivo , 2010, Molecular and Cellular Biochemistry.

[99]  M. Pollak.  Metformin and Other Biguanides in Oncology: Advancing the Research Agenda , 2010, Cancer Prevention Research.

[100]  Y. Lu,et al.  Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). , 2001, Journal of the National Cancer Institute.

[101]  Paul G. Gauger,et al.  Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling , 2009, Clinical Cancer Research.

[102]  D. Flieder,et al.  Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors , 2008, Proceedings of the National Academy of Sciences.

[103]  D. Leroith,et al.  The role of the IGF system in cancer growth and metastasis: overview and recent insights. , 2007, Endocrine reviews.

[104]  C. Braconi,et al.  Molecular targets in Gastrointestinal Stromal Tumors (GIST) therapy. , 2008, Current cancer drug targets.

[105]  B. Leyland-Jones,et al.  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. , 2006, Cancer research.

[106]  Z. Gucev,et al.  Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells. , 1996, Cancer research.

[107]  M. Pollak,et al.  Insulin and insulin-like growth factor signalling in neoplasia , 2008, Nature Reviews Cancer.

[108]  Federica Madia,et al.  Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans , 2011, Science Translational Medicine.

[109]  R. Sills,et al.  Inhibition of the insulin-like growth factor 1 receptor pathway enhances the antitumor effect of cisplatin in human malignant mesothelioma cell lines. , 2009, Cancer letters.

[110]  J. Strausz,et al.  Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). , 2010 .

[111]  P. Glazer,et al.  ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[112]  S. Novello,et al.  Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[113]  S. Ezzat,et al.  Acromegaly: Re-thinking the cancer risk , 2008, Reviews in Endocrine and Metabolic Disorders.

[114]  R. Kurzrock,et al.  A Phase I Study of Weekly R1507, A Human Monoclonal Antibody Insulin-like Growth Factor-I Receptor Antagonist, in Patients with Advanced Solid Tumors , 2010, Clinical Cancer Research.

[115]  P. Jedlicka,et al.  A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs , 2011, Oncogene.

[116]  K. Højlund,et al.  Circulating levels of insulin-like growth factor-II/mannose-6-phosphate receptor in obesity and type 2 diabetes. , 2010, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[117]  W. Daughaday,et al.  Somatomedin: Proposed Designation for Sulphation Factor , 1972, Nature.

[118]  E. Buck,et al.  Small molecule inhibitors of the IGF-1R/IR axis for the treatment of cancer , 2011, Expert opinion on investigational drugs.

[119]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[120]  Z. Laron,et al.  Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. , 2011, European journal of endocrinology.

[121]  F. Laube.  Mannose-6-phosphate/insulin-like growth factor-II receptor in human melanoma cells: effect of ligands and antibodies on the receptor expression. , 2009, Anticancer research.

[122]  M. Tabrizi,et al.  Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth. , 2011, Cancer research.

[123]  L. Helman,et al.  Targeting IGF-1R in the treatment of sarcomas: past, present and future. , 2009, Bulletin du cancer.

[124]  D. Leroith,et al.  Minireview: IGF, Insulin, and Cancer. , 2011, Endocrinology.

[125]  M. Yaffe,et al.  Insulin-Like Growth Factor-I, IGF-Binding Protein-3, and Mammographic Breast Density , 2005, Cancer Epidemiology Biomarkers & Prevention.

[126]  F. Heppner,et al.  Antisense treatment of IGF-IR induces apoptosis and enhances chemosensitivity in central nervous system atypical teratoid/rhabdoid tumours cells. , 2007, European journal of cancer.