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Updated: Sep 29, 2025
High-Throughput In Vitro Assay using Patient-Derived Tumor Organoids
Published on: June 14, 2021
Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures
Katharina Wang1, Ina Schütze2, Sebastian Gulde3
1Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany.
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.
Insights
Aggressive pheochromocytomas and paragangliomas (PPGLs) treatment shows promise with targeted therapies. Certain drugs and combinations, like cabozantinib/everolimus, are effective, especially in metastatic and SDHB-mutant tumors.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Aggressive pheochromocytomas and paragangliomas (PPGLs) present treatment challenges.
- Molecular targeting offers potential but yields variable results.
- Understanding drug responsivity in distinct PPGL subtypes is crucial.
Purpose of the Study:
- To investigate the efficacy of established and novel molecular-targeted drugs and chemotherapeutic agents against PPGLs.
- To compare drug responsivity between pseudohypoxia-associated (cluster 1) and kinase signaling-associated (cluster 2) PPGL subtypes.
- To identify promising targeted therapies and combinations for aggressive PPGLs.
Main Methods:
- Utilized human primary PPGL cultures and murine cell line spheroids from 33 patients (including 7 metastatic).
- Identified driver mutations in 79% of PPGLs to stratify patients into cluster 1 (n=10) and cluster 2 (n=14).
- Assessed the efficacy of single agents and combination therapies, including novel molecular-targeted drugs.
Main Results:
- Single agents like cabozantinib, selpercatinib, and 5-FU were more effective in cluster 1; high-dose estrogen and low-dose zoledronic acid in cluster 2.
- Everolimus, sunitinib, and others showed similar efficacy across both clusters.
- Cabozantinib/everolimus, alpelisib/everolimus, and alpelisib/trametinib combinations demonstrated efficacy, with some showing synergistic effects.
- Cabozantinib/everolimus, gemcitabine, and high-dose zoledronic acid showed high efficacy in SDHB-mutant and metastatic tumors.
Conclusions:
- Minor differences in drug responsivity exist between cluster 1 and cluster 2 PPGLs.
- Targeted combination therapies, particularly cabozantinib/everolimus, show significant promise for aggressive and metastatic PPGLs.
- Gemcitabine and high-dose zoledronic acid are also promising options for specific PPGL subtypes.
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