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: 6.21). 11/2008; 94(1):204-12. DOI: 10.1210/jc.2008-1456
Source: PubMed


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.

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    • "Logié et al. were the first to report that antibodies against IGF2 and IGF1R inhibit the proliferation of H295R cells [16]. More recently, it has been demonstrated that an anti-IGFR1 monoclonal antibody (IMC-A12) or a tyrosine kinase inhibitor specific for IGF1R (NVP-AEW541) are able to inhibit the proliferation of H295R cells both in vitro and in mouse xenografts [18]. This growth-promoting effect has also been demonstrated in other adrenocortical tumor cell lines: SW-13 cells do not express high levels of IGF2 and mouse Y1 cells do not express IGF1R; however, SW-13 cells proliferate rapidly in the presence of IGF2 [35] and Y1 cells proliferate rapidly when IGF1R is overexpressed [36]. "
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    ABSTRACT: Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.
    PLoS ONE 08/2014; 9(8):e103744. DOI:10.1371/journal.pone.0103744 · 3.23 Impact Factor
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    • "As IGFs have been defined as major contributors of ACT growth (Giordano et al., 2003; Weber et al., 1997), targeting of type I insulin-like growth factor receptor (IGF1R) dependent pathways represents a promising approach to modulate the proliferative phenotype of ACC cells. In accordance with this notion Barlaskar and colleagues could demonstrate that treatment of animals bearing NCI-H295 derived subcutaneous tumors with IGF1R antagonistic compounds resulted in a significant amelioration of tumor growth and increase in survival time (Barlaskar et al., 2009). These experiments among others have paved the way for current clinical trials exploring the efficacy of IGF blockage in patients with ACC. "

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    • "These facts make the IGF system an interesting target to pharmacological inhibition. Preclinical studies with pharmacological inhibitors of IGF1R have demonstrated a significant antiproliferative effect (Almeida, Fragoso et al. 2008, Barlaskar, Spalding et al. 2009). Early clinical trials with IGF1R inhibitors have demonstrated beneficial effects in some patients with advanced disease (Haluska, Worden et al. 2010). "
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    ABSTRACT: Adrenocortical tumors are common neoplasms. Most are benign, nonfunctional and clinically irrelevant. However, adrenocortical carcinoma is a rare disease with a dismal prognosis and no effective treatment apart from surgical resection. The molecular genetics of adrenocortical tumors remain poorly understood. For decades, molecular studies relied on a small number of samples and were directed to candidate-genes. This approach, based on the elucidation of the genetics of rare genetic syndromes in which adrenocortical tumors are a manifestation, has led to the discovery of major dysfunctional molecular pathways in adrenocortical tumors, such as the IGF pathway, the Wnt pathway and TP53. However, with the advent of high-throughput methodologies and the organization of international consortiums to obtain a larger number of samples and high-quality clinical data, this paradigm is rapidly changing. In the last decade, genome-wide expression profile studies, microRNA profiling and methylation profiling allowed the identification of subgroups of tumors with distinct genetic markers, molecular pathways activation patterns and clinical behavior. As a consequence, molecular classification of tumors has proven to be superior to traditional histological and clinical methods in prognosis prediction. In addition, this knowledge has also allowed the proposal of molecular-targeted approaches aiming better treatment options for advanced disease. This review aims to summarize the most relevant data on the rapidly evolving field of genetics of adrenal disorders.
    Molecular and Cellular Endocrinology 11/2013; 386(1-2). DOI:10.1016/j.mce.2013.10.028 · 4.41 Impact Factor
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