Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

Author:

Wang Katharina1ORCID,Schütze Ina2,Gulde Sebastian3,Bechmann Nicole45ORCID,Richter Susan4ORCID,Helm Jana5,Lauseker Michael6,Maurer Julian1,Reul Astrid2,Spoettl Gerald1,Klink Barbara789,William Doreen9,Knösel Thomas10,Friemel Juliane11,Bihl Michel11ORCID,Weber Achim11,Fankhauser Maria1,Schober Laura1,Vetter Diana12,Broglie Däppen Martina13,Ziegler Christian G5ORCID,Ullrich Martin14ORCID,Pietzsch Jens1415,Bornstein Stefan R5,Lottspeich Christian1,Kroiss Matthias116ORCID,Fassnacht Martin16,Wenter Vera Ursula Julia17ORCID,Ladurner Roland18,Hantel Constanze25,Reincke Martin1,Eisenhofer Graeme45,Grossman Ashley B1920,Pacak Karel21ORCID,Beuschlein Felix12,Auernhammer Christoph J1,Pellegata Natalia S3,Nölting Svenja12ORCID

Affiliation:

1. 1Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

2. 2Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

3. 3Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

4. 4Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

5. 5Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

6. 6Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig Maximilian University of Munich, Munich, Germany

7. 7Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

8. 8National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg

9. 9German Cancer Consortium, Dresden, Germany

10. 10Institute of Pathology, Ludwig Maximilian University of Munich, Munich, Germany

11. 11Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland

12. 12Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland

13. 13Department of Otorhinolaryngology, University Hospital Zurich, Zurich, Switzerland

14. 14Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

15. 15Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany

16. 16Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital Würzburg, University of Würzburg, Würzburg, Germany

17. 17Department of Nuclear Medicine, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

18. 18Department of General-, Visceral-, and Transplant-Surgery, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

19. 19Green Templeton College, University of Oxford, Oxford, UK

20. 20NET Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK

21. 21Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Abstract

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.

Publisher

Bioscientifica

Subject

Cancer Research,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism

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