In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma.
OBJECTIVE
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.


METHODS
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-gamma, 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.
Klopper
Joshua P
JP
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA. joshua.klopper@uchsc.edu
Berenz
Andrew
A
Hays
William R
WR
Sharma
Vibha
V
Pugazhenthi
Umarani
U
Janssen
Jennifer
J
Singh
Meenakshi
M
Bissonnette
Reid P
RP
Haugen
Bryan R
BR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077610:Bexarotene; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene