Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma.

CONTEXT Drug therapy for adrenocortical carcinoma (ACC), a rare and lethal malignancy, is largely empirical and ineffective. New treatments directed at molecular targets critical to the pathophysiology of ACC may prove more efficacious. OBJECTIVE The objective of the study was to profile human adrenal tumors and ACC cell lines to assess activated IGF signaling and determine the efficacy of two IGF receptor (IGF-1R) antagonists alone and in combination with mitotane. EXPERIMENTAL DESIGN ACC cell lines that display or lack activated IGF signaling are used to assess the effects of two IGF-1R antagonists in cultured cells and ACC xenograft tumors. RESULTS Transcriptional profiling data derived from DNA microarray analysis of human adrenal tumors implicate IGF2 as the single highest up-regulated transcript in the vast majority of carcinomas. We show that the majority of ACC cell lines tested display constitutive IGF ligand production and activation of downstream effector pathways. Both IGF-1R antagonists cause significant dose-dependent growth inhibition in ACC cell lines. Furthermore, we observe that mitotane, the first-line adrenolytic drug used in patients with ACC, results in enhanced growth inhibition when used in combination with the IGF-1R antagonists. We next examined the activity of IGF-1R antagonists against ACC xenografts in athymic nude mice. IGF inhibition markedly reduced tumor growth greater than that observed with mitotane treatment, and combination therapy with mitotane significantly enhanced tumor growth suppression. CONCLUSION These findings establish a critical role of IGF signaling in ACC pathophysiology and provide rationale for use of targeted IGF-1R antagonists to treat adrenocortical carcinoma in future clinical trials.

[1]  V. Gorgoulis,et al.  p57KIP2: “Kip”ing the Cell under Control , 2009, Molecular Cancer Research.

[2]  S. Ng,et al.  Phosphatidylinositol 3-Kinase Signaling Does Not Activate the Wnt Cascade , 2009, The Journal of Biological Chemistry.

[3]  H. Lehrach,et al.  DNA methylation in the IGF2 intragenic DMR is re-established in a sex-specific manner in bovine blastocysts after somatic cloning. , 2009, Genomics.

[4]  M. Bartolomei.  Genomic imprinting: employing and avoiding epigenetic processes. , 2009, Genes & development.

[5]  L. Chodosh,et al.  mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. , 2009, Cell stem cell.

[6]  Xi He,et al.  Wnt/beta-catenin signaling: components, mechanisms, and diseases. , 2009, Developmental cell.

[7]  J. Scheys,et al.  In search of adrenocortical stem and progenitor cells. , 2009, Endocrine reviews.

[8]  F. Speleman,et al.  Aberrant methylation of candidate tumor suppressor genes in neuroblastoma. , 2009, Cancer letters.

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

[10]  Jane Sun,et al.  Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. , 2008, Cellular signalling.

[11]  C. Lotfi,et al.  Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. , 2008, The Journal of clinical endocrinology and metabolism.

[12]  A. Gabory,et al.  The H19 locus acts in vivo as a tumor suppressor , 2008, Proceedings of the National Academy of Sciences.

[13]  G. Hammer,et al.  Targeted disruption of β-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex , 2008, Development.

[14]  Yoko Ito,et al.  Distinct Methylation Changes at the IGF2-H19 Locus in Congenital Growth Disorders and Cancer , 2008, PloS one.

[15]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells , 2008, Cell.

[16]  K. Asare.  Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient , 2007, Pharmacotherapy.

[17]  G. Hammer,et al.  Genetic removal of Smad3 from inhibin-null mice attenuates tumor progression by uncoupling extracellular mitogenic signals from the cell cycle machinery. , 2007, Molecular endocrinology.

[18]  J. Bourhis,et al.  Mechanisms of Disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer , 2007, Nature Clinical Practice Oncology.

[19]  D. Ludwig,et al.  IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor , 2007, Clinical Cancer Research.

[20]  A. Hochberg,et al.  The H19 Non-Coding RNA Is Essential for Human Tumor Growth , 2007, PloS one.

[21]  I. Gut,et al.  Rapid identification of promoter hypermethylation in hepatocellular carcinoma by pyrosequencing of etiologically homogeneous sample pools. , 2007, The Journal of molecular diagnostics : JMD.

[22]  Sean C. Bendall,et al.  IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro , 2007, Nature.

[23]  Xianglin Shi,et al.  AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. , 2007, Cancer research.

[24]  D. Schteingart.  Adjuvant mitotane therapy of adrenal cancer - use and controversy. , 2007, The New England journal of medicine.

[25]  M. Papotti,et al.  Adjuvant mitotane treatment for adrenocortical carcinoma. , 2007, The New England journal of medicine.

[26]  A. Feinberg.  Phenotypic plasticity and the epigenetics of human disease , 2007, Nature.

[27]  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.

[28]  J. Chung,et al.  Analysis of the H19ICR Insulator , 2007, Molecular and Cellular Biology.

[29]  B. Cullen,et al.  The imprinted H19 noncoding RNA is a primary microRNA precursor. , 2007, RNA.

[30]  P. Harari,et al.  Insulin-like growth factor-I receptor signaling blockade combined with radiation. , 2007, Cancer research.

[31]  E. Lalli,et al.  Gene expression profiling of childhood adrenocortical tumors. , 2007, Cancer research.

[32]  D. Yee,et al.  Disrupting insulin-like growth factor signaling as a potential cancer therapy , 2007, Molecular Cancer Therapeutics.

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

[34]  L. Parada,et al.  Development of a steroidogenic factor 1/Cre transgenic mouse line , 2006, Genesis.

[35]  Rolf Ohlsson,et al.  CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Prawitt,et al.  Beckwith–Wiedemann syndrome: multiple molecular mechanisms , 2006, Expert Reviews in Molecular Medicine.

[37]  Martin Fassnacht,et al.  Adrenocortical Carcinoma: Clinical Update , 2006 .

[38]  D. Bartsch,et al.  Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. , 2006, European journal of endocrinology.

[39]  A. Gabory,et al.  The H19 gene: regulation and function of a non-coding RNA , 2006, Cytogenetic and Genome Research.

[40]  M. Bartolomei,et al.  Developmental Profile of H19 Differentially Methylated Domain (DMD) Deletion Alleles Reveals Multiple Roles of the DMD in Regulating Allelic Expression and DNA Methylation at the Imprinted H19/Igf2 Locus , 2006, Molecular and Cellular Biology.

[41]  T. Iwama,et al.  A case of familial adenomatous polyposis complicated by thyroid carcinoma, carcinoma of the ampulla of vater and adrenocortical adenoma , 1991, The Japanese journal of surgery.

[42]  H. Clevers.  Wnt/beta-catenin signaling in development and disease. , 2006, Cell.

[43]  L. Kirschner.  Emerging treatment strategies for adrenocortical carcinoma: a new hope. , 2006, The Journal of clinical endocrinology and metabolism.

[44]  A. Feinberg,et al.  The epigenetic progenitor origin of human cancer , 2006, Nature Reviews Genetics.

[45]  Joakim Lundeberg,et al.  Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. , 2005, Surgery.

[46]  J. Bertherat,et al.  Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. , 2005, European journal of endocrinology.

[47]  J. Bertherat,et al.  Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. , 2005, Cancer research.

[48]  W. Linehan,et al.  Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. , 2005, Cancer research.

[49]  A. Feinberg,et al.  Loss of Imprinting of Igf2 Alters Intestinal Maturation and Tumorigenesis in Mice , 2005, Science.

[50]  B. Groner,et al.  The IGF-1 receptor and its contributions to metastatic tumor growth—novel approaches to the inhibition of IGF-1R function , 2005, Growth factors.

[51]  F. Berger,et al.  Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. , 2005, The Journal of clinical endocrinology and metabolism.

[52]  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.

[53]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[54]  I. Gut,et al.  De novo quantitative bisulfite sequencing using the pyrosequencing technology. , 2004, Analytical biochemistry.

[55]  Wolf Reik,et al.  Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops , 2004, Nature Genetics.

[56]  Yun‐Sil Lee,et al.  Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. , 2004, The Journal of investigative dermatology.

[57]  A. Hoeflich,et al.  Role of the Insulin-like Growth Factor System in Adrenocortical Growth Control and Carcinogenesis , 2004, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[58]  Michael Koutsilieris,et al.  The Akt pathway: molecular targets for anti-cancer drug development. , 2004, Current cancer drug targets.

[59]  A. Schatzkin,et al.  Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women. , 2004, Journal of the National Cancer Institute.

[60]  D. Fabbro,et al.  In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. , 2004, Cancer cell.

[61]  R. Ivanova,et al.  Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours. , 2004, European journal of endocrinology.

[62]  S. Apostolidou,et al.  An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. , 2003, Human molecular genetics.

[63]  Peter Bohlen,et al.  A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. , 2003, Cancer research.

[64]  Tony Hunter,et al.  Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. , 2003, Cancer cell.

[65]  K A Baggerly,et al.  Sensitive and quantitative universal Pyrosequencing methylation analysis of CpG sites. , 2003, BioTechniques.

[66]  A. Swain,et al.  Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad. , 2003, Molecular endocrinology.

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

[68]  Paul G Gauger,et al.  Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. , 2003, The American journal of pathology.

[69]  Linda Ng,et al.  Adrenocortical carcinoma: diagnosis, evaluation and treatment. , 2003, The Journal of urology.

[70]  M. Osaki,et al.  Evaluation of the antiangiogenic effect of Taxol in a human epithelial ovarian carcinoma cell line , 2003, Cancer Chemotherapy and Pharmacology.

[71]  G. Chrousos,et al.  The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. , 2002, The Journal of clinical endocrinology and metabolism.

[72]  J. Papkoff,et al.  Regulation of epithelial cell migration and tumor formation by beta-catenin signaling. , 2002, Experimental cell research.

[73]  G. Patrinos,et al.  DNA hypermethylation: when tumour suppressor genes go silent , 2002, Human Genetics.

[74]  LAWRENCE S. KIRSCHNER,et al.  Signaling Pathways in Adrenocortical Cancer , 2002, Annals of the New York Academy of Sciences.

[75]  M. Bartolomei,et al.  Analysis of Sequence Upstream of the Endogenous H19 Gene Reveals Elements Both Essential and Dispensable for Imprinting , 2002, Molecular and Cellular Biology.

[76]  A. Veronese,et al.  Loss of methylation at chromosome 11p15.5 is common in human adult tumors , 2002, Oncogene.

[77]  W. Reik,et al.  An intragenic methylated region in the imprinted Igf2 gene augments transcription , 2001, EMBO reports.

[78]  E. Baudin,et al.  Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. , 2001, Cancer research.

[79]  T. Giordano,et al.  Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome. , 2001, The Journal of clinical endocrinology and metabolism.

[80]  W. Reik,et al.  An upstream repressor element plays a role in Igf2 imprinting , 2001, The EMBO journal.

[81]  D. Livingston,et al.  Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity. , 2001, Molecular cell.

[82]  Y. Chapuis,et al.  Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group , 2001, World Journal of Surgery.

[83]  C. Weston,et al.  Signal transduction: signaling specificity- a complex affair. , 2001, Science.

[84]  F. Bertrand,et al.  Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. , 2001, Oncogene.

[85]  M. Herlyn,et al.  Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways. , 2001, Cancer research.

[86]  R. Reznek,et al.  Adrenal masses are associated with familial adenomatous polyposis , 2000, Diseases of the colon and rectum.

[87]  W. Reik,et al.  Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19 , 2000, Nature Genetics.

[88]  G. Felsenfeld,et al.  Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene , 2000, Nature.

[89]  A. Ferguson-Smith,et al.  Increased IGF-II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith-Wiedemann syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[90]  G. Capellá,et al.  DNA copy number changes and evaluation of MYC, IGF1R, and FES amplification in xenografts of pancreatic adenocarcinoma. , 2000, Cancer genetics and cytogenetics.

[91]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

[92]  C. Gicquel,et al.  Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. , 1999, Journal of molecular endocrinology.

[93]  E. Wolf,et al.  Postnatal Overexpression of Insulin-Like Growth Factor II in Transgenic Mice Is Associated with Adrenocortical Hyperplasia and Enhanced Steroidogenesis * , 1999 .

[94]  M. Bartolomei,et al.  Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. , 1998, Genes & development.

[95]  N. Ferrara,et al.  Corticotropin regulates vascular endothelial growth factor expression in human fetal adrenal cortical cells. , 1998, The Journal of clinical endocrinology and metabolism.

[96]  A. Hoffman,et al.  Modulation of Igf2 genomic imprinting in mice induced by 5-azacytidine, an inhibitor of DNA methylation. , 1997, Molecular endocrinology.

[97]  T. Moore,et al.  Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[98]  W. Reik,et al.  Transactivation of Igf2 in a mouse model of Beckwith–Wiedemann syndrome , 1997, Nature.

[99]  T. Noda,et al.  Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. , 1997, Science.

[100]  J. Church,et al.  Adrenal masses in patients with familial adenomatous polyposis , 1997, Diseases of the colon and rectum.

[101]  X. Bertagna,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Structural and Functional Abnormalities at 11p15 Are Associated with the Malignant Phenotype in Sporadic Adrenocortical Tumors: Study on a Series , 2022 .

[102]  S. Elledge,et al.  Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith–Wiedemann syndrome , 1997, Nature.

[103]  G. Chrousos,et al.  Extensive personal experience: adrenocortical tumors. , 1997, The Journal of clinical endocrinology and metabolism.

[104]  W. Kiess,et al.  Insulin-like growth factor receptors in normal and tumorous adult human adrenocortical glands. , 1997, European journal of endocrinology.

[105]  N. Miller,et al.  Biallelic expression of the IGF2 gene in human breast disease. , 1996, Human molecular genetics.

[106]  T. Hattori,et al.  Cell proliferation and renewal of mouse adrenal cortex. , 1996, Journal of anatomy.

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

[108]  D. Hanahan,et al.  Deregulation of both imprinted and expressed alleles of the insulin–like growth factor 2 gene during β–cell tumorigenesis , 1995, Nature Genetics.

[109]  A. Monaco,et al.  Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism , 1994, Nature.

[110]  W. Reik,et al.  Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes. , 1994, Development.

[111]  A. Feinberg,et al.  The genetics of BWS associated tumors , 1999 .

[112]  W. Miller,et al.  Steroidogenic adrenocortical cell lines produced by genetically targeted tumorigenesis in transgenic mice. , 1994, Molecular endocrinology.

[113]  V. Ilvesmäki,et al.  Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. , 1993, The Journal of clinical endocrinology and metabolism.

[114]  V. Han,et al.  Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II. , 1992, Endocrinology.

[115]  M. Melamed,et al.  Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. , 1990, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[116]  T. Triche,et al.  Establishment and characterization of a human adrenocortical carcinoma cell line that expresses multiple pathways of steroid biosynthesis. , 1990, Cancer research.

[117]  V. Han,et al.  Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. , 1988, The Journal of clinical endocrinology and metabolism.

[118]  Nan Faion T. Wu,et al.  The Beckwith-Wiedemann Syndrome , 1974, Clinical pediatrics.

[119]  A. Leibovitz,et al.  New human cancer cell culture lines. I. SW-13, small-cell carcinoma of the adrenal cortex. , 1973, Journal of the National Cancer Institute.

[120]  V. Buonassisi,et al.  Clonal analysis of differentiated function in animal cell cultures. I. Possible correlated maintenance of differentiated function and the diploid karyotype. , 1966, Cancer research.

[121]  J. Furth,et al.  Histologic and physiologic characteristics of hormone-secreting transplantable adrenal tumors in mice and rats. , 1957, The American journal of pathology.