Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications.

Iuliu Sbiera,Iuliu Sbiera,Stefan Kircher,Silviu Sbiera,Martin Fassnacht,Constanze Hantel,Matthias Kroiss,Matthias Kroiss,Matthias Kroiss,Matthias Kroiss,Barbara Altieri,Kerstin Lenz

doi:10.3389/fendo.2021.795116

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

Highlights

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, the pathogenesis of which is still poorly understood
Three normal adrenal glands (NAG), 15 adrenocortical adenomas (ACA) and 21 ACC were used for the Realtime PCR experiments as frozen samples, and three NAG, 21 ACA and 142 ACC were used for RNAScope as Formalin fixed, paraffin embedded (FFPE) tissue samples (Table 1)
Similarity matrix clustering of real-time RT-PCR assessment comprising 93 genes from the fibroblast growth factor (FGF) pathway showed a distinctive phenotype of adrenocortical tissue compared to all the other tissue samples (Figure 2)

Summary

Introduction

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, the pathogenesis of which is still poorly understood. Complete surgical resection is the treatment of choice in localized ACC and virtually the only option to achieve cure. Adjuvant therapy is recommended in most patients [1, 2]. The use of mitotane for adjuvant ACC treatment is mainly based on a large retrospective multicentre study conducted in Italy and Germany [3, 4]. The first and largest randomized phase III study in advanced ACC established etoposide, doxorubicin, cisplatin plus mitotane (EDP-M) as the cytotoxic chemotherapy of first choice [5]. There has been a growing interest in targeted therapies for the treatment of ACC

Methods

Results

Conclusion