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Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma
Ferdous M Barlaskar1, Aaron C Spalding, Joanne H Heaton
1Department 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.
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.
Insights
Targeting insulin-like growth factor (IGF) signaling with IGF receptor (IGF-1R) antagonists shows promise for treating adrenocortical carcinoma (ACC). Combination therapy with mitotane enhanced tumor growth suppression in preclinical models.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Adrenocortical carcinoma (ACC) is a rare, lethal malignancy with limited effective drug therapies.
- Current treatments for ACC are largely empirical and often ineffective.
- Targeted therapies addressing ACC's molecular drivers offer potential for improved efficacy.
Purpose of the Study:
- To profile human adrenal tumors and ACC cell lines for activated Insulin-like Growth Factor (IGF) signaling.
- To evaluate the efficacy of IGF receptor (IGF-1R) antagonists in ACC.
- To assess the combination therapy of IGF-1R antagonists with mitotane for ACC treatment.
Main Methods:
- DNA microarray analysis of human adrenal tumors to identify upregulated transcripts.
- Assessment of IGF signaling pathway activation in ACC cell lines.
- In vitro and in vivo studies using IGF-1R antagonists and mitotane on ACC cell lines and xenografts.
Main Results:
- IGF2 was the most significantly upregulated transcript in the majority of ACCs.
- Most ACC cell lines exhibited constitutive IGF ligand production and downstream pathway activation.
- IGF-1R antagonists demonstrated dose-dependent growth inhibition of ACC cells and xenografts.
- Combination therapy with mitotane significantly enhanced tumor growth suppression compared to either agent alone.
Conclusions:
- IGF signaling plays a critical role in the pathophysiology of adrenocortical carcinoma.
- Targeted IGF-1R antagonists represent a promising therapeutic strategy for ACC.
- These findings provide a strong rationale for the clinical investigation of IGF-1R antagonists in ACC treatment.
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