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

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures.

Endocr. Relat. Cancer 29, 285-306 (2022)

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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- (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, 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, 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-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 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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