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


METHODS
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.


CONCLUSIONS
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.
Department of Internal Medicine-Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, 1502 BSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA.
Ferdous M
FM
Barlaskar
Aaron C
AC
Spalding
Joanne H
JH
Heaton
Rork
R
Kuick
Alex C
AC
Kim
Dafydd G
DG
Thomas
Thomas J
TJ
Giordano
Edgar
E
Ben-Josef
Gary D
GD
Hammer
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D051379:Mice; D008939:Mitotane / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D007335:Insulin-Like Growth Factor II; D008939:Mitotane; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt