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In vivo and Microarray Analysis of Rexinoid-Responsive Anaplastic Thyroid Carcinoma

Authors' Affiliations: ¹ Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, and ² Department of Pathology, ³ University of Colorado Cancer Center, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado; and ⁴ Department of Molecular Oncology, Ligand Pharmaceuticals, San Diego, California

Requests for reprints: Joshua P. Klopper, Department of Medicine, University of Colorado at Denver and Health Sciences Center, MS 8106, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-1454; Fax: 303-724-3920; E-mail: joshua.klopper{at}uchsc.edu.

Purpose: Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor–selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis.

Experimental Design: Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes.

Results: DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis.

Conclusions: LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment.