Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures. Issue 6 (9th May 2022)

• Record Type: Journal Article
• Authors: 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; Lottspeich, Christian; Kroiss, Matthias; Fassnacht, Martin; Wenter, Vera Ursula Julia; Ladurner, Roland; Hantel, Constanze; Reincke, Martin; Eisenhofer, Graeme; Grossman, Ashley B; Pacak, Karel; Beuschlein, Felix; Auernhammer, Christoph J; Pellegata, Natalia S; Nölting, Svenja;
• Is Part Of: Endocrine-related cancer. Volume 29:Issue 6(2022)
• Page Start: 285
• Page End: 306
• Publication Date: 2022-05-09
• Subjects: personalized drug testing -- pheochromocytoma/paraganglioma -- human primary cultures -- 3D spheroid models -- somatic mutations; Endocrine glands -- Cancer -- Periodicals; Endocrinology -- Periodicals; Cancer -- Endocrine aspects -- Periodicals; 616.9944005
• DOI: 10.1530/ERC-21-0355
• Languages: English
• ISSNs: 1351-0088

Abstract

Abstract : 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 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 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.