SFEBES2019 POSTER PRESENTATIONS Endocrine Neoplasia and Endocrine Consequences of Living with and Beyond Cancer (36 abstracts)
PLK1 inhibitors as potential new treatment for adrenocortical carcinoma
Gabrielle Smith 1 , Raimunde Liang 2 , Vasileios Chortis 1 , Juliane Lippert 2 , Constanze Hantel 3 , Barbara Altieri 2 , Martin Fassnacht 2 , Paul Foster 1 & Cristina Ronchi 1,
1University of Birmingham, Birmingham, United Kingdom; 2University Hospital of Wuerzburg, Wuerzburg, Germany; 3University Hospital Zurich, Zurich, Switzerland
Background: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with limited treatment options for advanced stages. By targeted RNA expression screening, we identified polo-like kinase 1 (PLK1) as one of most overexpressed genes, thus representing a potential drug target for ACC. PLK1 inhibitors are under evaluation in clinical trials for other solid cancers and seem to be more effective in TP53 mutated tumours. The aim of the study was to evaluate PLK1 protein levels in a large series of ACC and test the efficacy of PLK1 inhibitors by functional experiments.
Methods: A total of 104 formalin-fixed paraffin-embedded tissue samples from ACC patients with available clinical and genetic data at tumour level were investigated. Nuclear PLK1 protein expression was evaluated by immunohistochemistry (anti-mouse monoclonal PLK1 antibody) and semi-quantitative H-score. Efficacy of PLK1-specific inhibitor Volasertib was tested in the standard NCI-H295R ACC cell line, which presents PLK-1 overexpression and TP53 deletion of exon 8 and 9, using different concentrations (50–200 nM) and time points (0, 48, 72 and 96 h). Cell proliferation was analysed using CyQUANT (Invitrogen).
Results: Nuclear PLK1 expression was classified as high in 59% of ACC samples, being more frequently elevated in TP53-mutated (n=24) than in TP53 wild type cases (n=80, 87.5 vs. 51%, P<0.01). No relationship was observed between PLK1 levels and either progression-free or overall survival. We found a concentration-dependent reduction of cell viability with in vitro dose response analysis, with a significant decrease in cell proliferation starting at 100 nM Volasertib treatment, compared to the vehicle control.
Conclusion: In this pilot study, we propose PLK1 inhibitors as promising candidates for treatment of a subset of ACC patients that may be pre-selected according to the tumour molecular pattern. We plan to extend functional experiments to further PLK1 inhibitors and further ACC cell lines with a different molecular profile.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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