Endocrine Abstracts

Background: Current drug treatment options for adrenocortical carcinoma (ACC) are rather limited and intensive efforts are going on to find novel effective agents. In our previous functional genomics study, retinoid signalling via the retinoid X receptor (RXR) was identified as a major pathogenic pathway in ACC and we have demonstrated the in vitro activity of 9-cis retinoic acid (9-cisRA) acting via the RXR on NCI-H295R cells and also found that 9-cisRA has antitumoural effects in a small pilot xenograft study.

Aim: To investigate the antitumoural effect of 9-cisRA and its combination with mitotane in a large-scale xenograft study.

Methods: 43 male SCID mice xenografted with NCI-H295R cells were treated in four groups (i) control – corn oil vehicle, ii) 5 mg/kg 9-cisRA, iii) 200 mg/kg mitotane, iv) 5 mg/kg 9-cisRA+200 mg/kg mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray (4×44 K Agilent Whole Genome Microarray) have been performed. Quantitative real-time-PCR (TaqMan) was used for the validation of the microarray results and to detect circulating microRNAs.

Results: Both 9-cisRA and mitotane reduced tumor growth relative to control, but only the combination of the two agents resulted in significant tumour size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Gene expression analysis revealed 483 genes with significant differences in expression, but only without Benjamini-Hochberg correction. Seven genes have been selected for validation by qRT-PCR, but only one (APOA4) was found significantly increased in the combined group compared with the control. The expression of circulating hsa-mir-483-5p was found significantly reduced in combined treatment relative to control.

Conclusions: Our results show that 9-cisRA might be a helpful additive in the treatment of ACC in combination with mitotane, but its mechanism of action awaits further investigations.

Disclosure: Hungarian Scientific Research Grant (OTKA K100295).