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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)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 3d Spheroid Models ; Human Primary Cultures ; Personalized Drug Testing ; Pheochromocytoma/paraganglioma ; Somatic Mutations
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 1351-0088
e-ISSN 1479-6821
Zeitschrift Endocrine-Related Cancer
Quellenangaben Band: 29, Heft: 6, Seiten: 285-306 Artikelnummer: , Supplement: ,
Verlag BioScientifica
Verlagsort Bristol
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502590-001
DOI 10.1530/ERC-21-0355
WOS ID WOS:000836579600002
Scopus ID 85130000622
PubMed ID 35324454
Erfassungsdatum 2022-08-30
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