Preclinical Targeting of the Type I Insulin-Like Growth Factor Receptor in Adrenocortical Carcinoma

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.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.31). 11/2008; 94(1):204-12. DOI: 10.1210/jc.2008-1456
Source: PubMed

ABSTRACT 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.
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.
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.
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.
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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Adrenocortical carcinoma (ACC) is a very rare and aggressive tumor with dismal outcomes. Best current treatments include complete surgical resection for localized resectable disease and systemic therapy with mitotane alone or in combination for advanced ACC. Advances in molecular genetic profiling of ACC have created multiple new targets for potential treatment options in ACC. This article reviews the current treatment options available for ACC and discusses the potential new targets identified through molecular profiling.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal.
    Frontiers in Endocrinology 02/2015; 6:23. DOI:10.3389/fendo.2015.00023
  • [Show abstract] [Hide abstract]
    ABSTRACT: A 48-year-old woman diagnosed with acromegaly 21 years earlier presented at our hospital with a left adrenal tumor. Her medical history included breast cancer, thyroid cancer and an incompletely resected growth hormone (GH)-producing pituitary adenoma. Endocrinological and radiological examinations revealed subclinical adrenal Cushing's syndrome. She subsequently underwent left adrenalectomy, followed by glucocorticoid replacement therapy. Her GH and insulin-like growth factor-1 levels were insufficiently controlled, and pegvisomant was administered in addition to octreotide acetate. Following adrenalectomy, a giant hepatic hemangioma and papillary thyroid carcinoma in the residual right lobe developed, indicating the high risk of tumor development in patients with acromegaly.
    Internal Medicine 01/2015; 54(6):617-20. DOI:10.2169/internalmedicine.54.2782 · 0.97 Impact Factor