TY - JOUR
T1 - Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures
AU - Wang, Katharina
AU - Schütze, Ina
AU - Gulde, Sebastian
AU - Bechmann, Nicole
AU - Richter, Susan
AU - Helm, Jana
AU - Lauseker, Michael
AU - Maurer, Julian
AU - Reul, Astrid
AU - Spoettl, Gerald
AU - Klink, Barbara
AU - William, Doreen
AU - Knösel, Thomas
AU - Friemel, Juliane
AU - Bihl, Michel
AU - Weber, Achim
AU - Fankhauser, Maria
AU - Schober, Laura
AU - Vetter, Diana
AU - Broglie Däppen, Martina
AU - Ziegler, Christian G.
AU - Ullrich, Martin
AU - Pietzsch, Jens
AU - Bornstein, Stefan R.
AU - Lottspeich, Christian
AU - Kroiss, Matthias
AU - Fassnacht, Martin
AU - Wenter, Vera Ursula Julia
AU - Ladurner, Roland
AU - Hantel, Constanze
AU - Reincke, Martin
AU - Eisenhofer, Graeme
AU - Grossman, Ashley B.
AU - Pacak, Karel
AU - Beuschlein, Felix
AU - Auernhammer, Christoph J.
AU - Pellegata, Natalia S.
AU - Nölting, Svenja
N1 - Publisher Copyright:
© 2022 Society for Endocrinology.
PY - 2022/6
Y1 - 2022/6
N2 - 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 primarycultures. 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 ov erall 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: s ome single anti-cancer drugs were more effective in cluster 1 and some targeted combina tion treatments were more effective in cluster 2.
AB - 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 primarycultures. 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 ov erall 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: s ome single anti-cancer drugs were more effective in cluster 1 and some targeted combina tion treatments were more effective in cluster 2.
KW - 3D spheroid models
KW - human primary cultures
KW - paraganglioma
KW - personalized drug testing
KW - pheochromocytoma/
KW - somatic mutations
UR - http://www.scopus.com/inward/record.url?scp=85130000622&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35324454
U2 - 10.1530/ERC-21-0355
DO - 10.1530/ERC-21-0355
M3 - Article
C2 - 35324454
AN - SCOPUS:85130000622
SN - 1351-0088
VL - 29
SP - 285
EP - 306
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
IS - 6
ER -