High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma.
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.
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH, Bethesda, Maryland, United States of America.
Alessio
A
Giubellino
Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
Uma
U
Shankavaram
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH, Bethesda, Maryland, United States of America; Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Petra
P
Bullova
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH, Bethesda, Maryland, United States of America; Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, University Hospital of Olomouc, Czech Republic.
Jan
J
Schovanek
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland, United States of America.
Yaqin
Y
Zhang
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland, United States of America.
Min
M
Shen
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH, Bethesda, Maryland, United States of America.
Nikita
N
Patel
National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Abdel
A
Elkahloun
Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
Min-Jung
MJ
Lee
Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
Jane
J
Trepel
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland, United States of America.
Marc
M
Ferrer
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH, Bethesda, Maryland, United States of America.
Karel
K
Pacak
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D055808:Drug Discovery; D058492:Drug Repositioning; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010235:Paraganglioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger