Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures


Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

Wang, K.; Schütze, I.; Gulde, S.; Bechmann, N.; Richter, S.; Helm, J.; Lauseker, M.; Maurer, J.; Reul, A.; Spöttl, G.; Klink, B.; William, D.; Knösel, T.; Friemel, J.; Bihl, M.; Weber, A.; Fankhauser, M.; Schober, L.; Vetter, D.; Broglie Däppen, M.; Ziegler, C. G.; Ullrich, M.; Pietzsch, J.; Bornstein, S. R.; Lottspeich, C.; Kroiß, M.; Fassnacht, M.; Wenter, V.; Ladurner, R.; Hantel, C.; Reincke, M.; Eisenhofer, G.; Grossman, A. B.; Pacak, K.; Beuschlein, F.; Auernhammer, C. J.; Pellegata, N.; Nölting, S.

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 82% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1- (n=11) 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, 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, gemcitabine, AR-A014418, high-dose zoledronic acid). 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-2α 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 in cluster 2 and overall synergistic effects (cabozantinib/everolimus, lpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be the very 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 targeted combination treatments were more effective in cluster 2.

Keywords: Personalized drug testing; pheochromocytoma/paraganglioma; human primary cultures; 3D spheroid models; somatic mutations

Permalink: https://www.hzdr.de/publications/Publ-34425
Publ.-Id: 34425