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Preclinical Targeting of the Type I Insulin-Like Growth Factor Receptor in Adrenocortical Carcinoma Ferdous M. Barlaskar, Aaron C. Spalding, Joanne H. Heaton, Rork Kuick, Alex C. Kim, Dafydd G. Thomas, Thomas J. Giordano, Edgar Ben-Josef, and Gary D. Hammer Department of Internal Medicine-Division of Metabolism, Endocrinology, and Diabetes (F.M.B., J.H.H., A.C.K., G.D.H.), Departments of Radiation Oncology (A.C.S., E.B.-J.) and Department of Pathology (D.G.T., T.J.G.) and Biostatistics Core, Comprehensive Cancer Center (R.K.), University of Michigan Medical School, Ann Arbor, Michigan 48109 Context: Drug ther apy for adre noco rtic al carc inoma (ACC), a rare and leth al mali gnancy , is larg ely empi rica l and inef fect ive. New trea tments dire cted at mole cul ar targ ets crit ical to the path ophy s- iology of ACC may prove more efficaci ous. 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 combin ation 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 carci- nomas.WeshowthatthemajorityofACCcelllinestesteddisplayconstitutiveIGFligandproduction and activation of downstream effector pathways. Both IGF-1R antagonists cause significant dose- depende nt growth inhibition in ACC cell lines. Furthermore , we observe that mitotane, the first- li ne adr eno lytic dru g use d in pat ien ts wi th ACC, res ul ts in enh anced gro wt h inhi bi tio n when use d 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 prov iderationalefor useof targ etedIGF-1 R anta goniststo treat adrenoc orti calcarcinomain future clinica l trials. (  J Clin Endocrinol Metab 94: 204–212, 2009) A drenocortical carcinoma (ACC) is a rare endocrine malig- nancy characterized by a limited understanding of its de- velopment and pathophysiology, dismal clinical prognosis, and lac k of eff ica cious the rapeuticreg ime ns.The ann ualincide nceof ACC ranges from 0.5 to 2 cases per millio n (1). Wherea s com- plete operative resectio n remains the only poten tially curative option for ACC, approximately half of all patients present with met astatic dis eas e (1, 2).This results in a 5-y r surviv al rate of les s than 10% (1, 3). A better understanding of the etiology and patho genes is of this devasta ting disease could lead to more ef- fectiv e drugdesigns and the develo pmentof molec ularlytargeted treatments. ACC’s associati on witha selectnumber of gen eti c syndromes such as Beckwith-Wiedemann syndrome (BWS) has provided insights into its pathophysiology. BWS arises from a loss of het- erozygosity and/or a loss of imprinting of the 11p15.5 chromo- somal reg ion . Thi s loc us inc lud es the mitogenic hor mon e, IGF -2 gene (IGF2), and locus dysregulation results in significant over- expression of this gene. Transcriptional profiling of sporadic ACC tissue s provi des additional support for this hormone’s ISSN Pr int 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/jc.2008-1456 Received July 8, 2008. Acce pted October 3, 2008. First Published Online October 14, 2008 Abbreviations: ACA, Adrenocortical adenoma; ACC, adrenocortical carcinoma; BWS, Beckwith-Wiedemann syndrome; FITC, fluorescein isothiocyanate; IGF-1R, IGF receptor; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carb oxymethoxyp henyl)-2-(4-sulfophenyl)-2H-tet- razolium; VEGF, vascular endothelial growth factor. O R I G I N A L A R T I C L E E n d o c r i n e C a r e 204 jcem.end ojou rnal s.org J Cl in Endocrinol Metab. Janu ary 2009 , 94 (1):204–212  at Biblioteca Area Biomedica Universita Tor Vergata on July 23, 2009  jcem.endojournals.org Downloaded from 

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