High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma

Alessio Giubellino, Uma Shankavaram, Petra Bullova, Jan Schovanek, Yaqin Zhang, Min Shen, Nikita Patel, Abdel Elkahloun, Min Jung Lee, Jane Trepel, Marc Ferrer, Karel Pacak

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Drug repurposing or repositioning is an important part of drug discovery that has been growing in the last few years for the development of therapeutic options in oncology. We applied this paradigm in a screening of a library of about 3,800 compounds (including FDA-approved drugs and pharmacologically active compounds) employing a model of metastatic pheochromocytoma, the most common tumor of the adrenal medulla in children and adults. The collection of approved drugs was screened in quantitative mode, testing the compounds in compound-titration series (dose-response curves). Analysis of the dose-response screening data facilitated the selection of 50 molecules with potential bioactivity in pheochromocytoma cells. These drugs were classified based on molecular/cellular targets and signaling pathways affected, and selected drugs were further validated in a proliferation assay and by flow cytometric cell death analysis. Using meta-analysis information from molecular targets of the top drugs identified by our screening with gene expression data from human and murine microarrays, we identified potential drugs to be used as single drugs or in combination. An example of a combination with a synergistic effect is presented. Our study exemplifies a promising model to identify potential drugs from a group of clinically approved compounds that can more rapidly be implemented into clinical trials in patients with metastatic pheochromocytoma or paraganglioma.

Original languageEnglish (US)
Article numbere90458
JournalPloS one
Volume9
Issue number4
DOIs
StatePublished - Apr 3 2014

Bibliographical note

Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.

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