Endocrine Abstracts

Introduction

Progressive and radioiodine-refractory thyroid cancer has poor outcomes and limited therapeutic options (i.e tyrosine kinase inhibitors) due to the transient efficacy of treatment and toxic effects. Therefore, combinatorial treatment with new therapeutic approaches are needed. Many studies link G Protein-Coupled Receptors (GPCRs) to cancer. The aim of this study is to present the first specific atlas of GPCRs expression in progressive and refractory thyroid cancer and identify new potential targets among theses GPCRs aiming at drug repositioning.

Methods

We analyzed samples from tumor and normal thyroid tissue from 17 patients with refractory thyroid cancer (twelve papillary thyroid cancers (PTC) and five follicular thyroid cancers (FTC)). We assessed the GPCR mRNA expression by using the NanoString technology with a custom panel of 371 GPCRs and we selected GPCRs differentially-expressed between normal and tumoral tissues. The data were compared with public repositories by bioinformatics analyses (GEO and TCGA data sets) and pharmacological databases. Finally, we screened approved drugs that target differentially-expressed GPCRs. Experiments were performed with primary human refractory thyroid cancer cells isolated from tumoral ascites by measuring cell viability (Cell Titer-Glo Luminescent Cell Viability Assay kit) and cell migration (IncuCyte S3 live cell imaging system).

Results

With our transcriptomic analysis, 4 receptors were down regulated in FTC (VIPR1, ADGRL2, ADGRA3 and ADGRV1). In PTC, 24 receptors were deregulated, seven of which identified also by bioinformatics analyses of published studies on primary thyroid cancers (VIPR1, ADORA1, GPRC5B, P2RY8, GABBR2, CYSLTR2 and LPAR5). Among all the differentially-expressed genes, 25 GPCRs are the target of approved drugs and some receptor feature was also associated with overall survival or progression-free survival. Drug screening in ascites-derived primary refractory thyroid cancer cells found three agents with antiproliferative effect and anti-migratory effect in the micromolar range.

Conclusions

For the first time, we performed GPCR mRNA expression profiling in progressive and refractory thyroid cancers. A preliminary drug screening identified candidate drugs that target GPCRs. These findings provide an opportunity to the identification of new therapeutic targets for drug repositioning and precision medicine in radioiodine-refractory thyroid cancer.