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Wang, Katharina; Schütze, Ina; Gulde, Sebastian; Bechmann, Nicole; Richter, Susan; Helm, Jana; Lauseker, Michael; Maurer, Julian; Reul, Astrid; Spoettl, Gerald; Klink, Barbara; William, Doreen; Knösel, Thomas; Friemel, Juliane; Bihl, Michel; Weber, Achim; Fankhauser, Maria; Schober, Laura; Vetter, Diana; Broglie Däppen, Martina; Ziegler, Christian G; Ullrich, Martin; Pietzsch, Jens; Bornstein, Stefan R; [...]

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

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  • Media type: E-Article
  • Title: Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures
  • Contributor: Wang, Katharina; Schütze, Ina; Gulde, Sebastian; Bechmann, Nicole; Richter, Susan; Helm, Jana; Lauseker, Michael; Maurer, Julian; Reul, Astrid; Spoettl, Gerald; Klink, Barbara; William, Doreen; Knösel, Thomas; Friemel, Juliane; Bihl, Michel; Weber, Achim; Fankhauser, Maria; Schober, Laura; Vetter, Diana; Broglie Däppen, Martina; Ziegler, Christian G; Ullrich, Martin; Pietzsch, Jens; Bornstein, Stefan R; [...]
  • imprint: Bioscientifica, 2022
  • Published in: Endocrine-Related Cancer
  • Language: Not determined
  • DOI: 10.1530/erc-21-0355
  • ISSN: 1351-0088; 1479-6821
  • Keywords: Cancer Research ; Endocrinology ; Oncology ; Endocrinology, Diabetes and Metabolism
  • Origination:
  • Footnote:
  • Description: <jats:p>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 (<jats:italic>n</jats:italic>  = 10) and kinase signaling-associated cluster 2-related (<jats:italic>n</jats:italic>  = 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 <jats:italic>SDHB</jats:italic>-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.</jats:p>
  • Access State: Open Access