Synergistic Highly Potent Targeted Drug Combinations in Different Pheochromocytoma Models Including Human Tumor Cultures

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Maria Fankhauser - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Nicole Bechmann - , Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Michael Lauseker - , Ludwig Maximilian University of Munich (Author)
  • Judith Goncalves - , Université Paris Cité (Author)
  • Judith Favier - , Université Paris Cité (Author)
  • Barbara Klink - , Institute of Clinical Genetics, German Cancer Consortium (Partner: DKTK, DKFZ), University Hospital Carl Gustav Carus Dresden, Laboratoire National de Santé (Author)
  • Doreen William - , German Cancer Consortium (Partner: DKTK, DKFZ) (Author)
  • Laura Gieldon - , German Cancer Consortium (Partner: DKTK, DKFZ), Institute of Clinical Genetics, University Hospital Carl Gustav Carus Dresden, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT) Dresden (Author)
  • Julian Maurer - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Gerald Spöttl - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Petra Rank - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Thomas Knösel - , Ludwig Maximilian University of Munich (Author)
  • Michael Orth - , University Hospital Münster (Author)
  • Christian G Ziegler - , Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden (Author)
  • Elke Tatjana Aristizabal Prada - , Department of internal Medicine I (Author)
  • German Rubinstein - , Department of internal Medicine I (Author)
  • Martin Fassnacht - , University Hospital Münster (Author)
  • Christine Spitzweg - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Ashley B Grossman - , University of Oxford (Author)
  • Karel Pacak - , National Institutes of Health (NIH) (Author)
  • Felix Beuschlein - , Hospital of the Ludwig-Maximilians-University (LMU) Munich, University Hospital Zurich (Author)
  • Stefan R Bornstein - , Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden (Author)
  • Graeme Eisenhofer - , Department of Internal Medicine III, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Christoph J Auernhammer - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Martin Reincke - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Svenja Nölting - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)

Abstract

There are no officially approved therapies for metastatic pheochromocytomas apart from ultratrace 131I-metaiodbenzylguanidine therapy, which is approved only in the United States. We have, therefore, investigated the antitumor potential of molecular-targeted approaches in murine pheochromocytoma cell lines [monocyte chemoattractant protein (MPC)/monocyte chemoattractant protein/3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], immortalized mouse chromaffin Sdhb-/- cells, three-dimensional pheochromocytoma tumor models (MPC/MTT spheroids), and human pheochromocytoma primary cultures. We identified the specific phosphatidylinositol-3-kinase α inhibitor BYL719 and the mammalian target of rapamycin inhibitor everolimus as the most effective combination in all models. Single treatment with clinically relevant doses of BYL719 and everolimus significantly decreased MPC/MTT and Sdhb-/- cell viability. A targeted combination of both inhibitors synergistically reduced MPC and Sdhb-/- cell viability and showed an additive effect on MTT cells. In MPC/MTT spheroids, treatment with clinically relevant doses of BYL719 alone or in combination with everolimus was highly effective, leading to a significant shrinkage or even a complete collapse of the spheroids. We confirmed the synergism of clinically relevant doses of BYL719 plus everolimus in human pheochromocytoma primary cultures of individual patient tumors with BYL719 attenuating everolimus-induced AKT activation. We have thus established a method to assess molecular-targeted therapies in human pheochromocytoma cultures and identified a highly effective combination therapy. Our data pave the way to customized combination therapy to target individual patient tumors.

Details

Original languageEnglish
Pages (from-to)2600-2617
Number of pages18
JournalEndocrinology
Volume160
Issue number11
Publication statusPublished - 1 Nov 2019
Peer-reviewedYes

External IDs

PubMedCentral PMC6795182
Scopus 85073310193
ORCID /0000-0002-6932-333X/work/148144982

Keywords

Keywords

  • Adrenal Gland Neoplasms/drug therapy, Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents/pharmacology, Antineoplastic Combined Chemotherapy Protocols, Cell Cycle/drug effects, Cell Line, Drug Screening Assays, Antitumor, Drug Synergism, Everolimus/pharmacology, Female, Humans, Male, Mice, Middle Aged, Pheochromocytoma/drug therapy, Primary Cell Culture, Signal Transduction/drug effects, Thiazoles/pharmacology