Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

in Endocrine-Related Cancer
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  • 1 Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany
  • | 2 Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
  • | 3 Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
  • | 4 Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  • | 5 Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany
  • | 6 Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig Maximilian University of Munich, Munich, Germany
  • | 7 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  • | 8 National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg
  • | 9 German Cancer Consortium, Dresden, Germany
  • | 10 Institute of Pathology, Ludwig Maximilian University of Munich, Munich, Germany
  • | 11 Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
  • | 12 Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland
  • | 13 Department of Otorhinolaryngology, University Hospital Zurich, Zurich, Switzerland
  • | 14 Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
  • | 15 Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany
  • | 16 Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital Würzburg, University of Würzburg, Würzburg, Germany
  • | 17 Department of Nuclear Medicine, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany
  • | 18 Department of General-, Visceral-, and Transplant-Surgery, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany
  • | 19 Green Templeton College, University of Oxford, Oxford, UK
  • | 20 NET Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
  • | 21 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Correspondence should be addressed to S Nölting: svenja.noelting@usz.ch

*(K Wang and I Schütze contributed equally to this work)

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Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n  = 10) and kinase signaling-associated cluster 2-related (n  = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

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