Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

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- (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.

The Management of Phaeochromocytomas and Paragangliomas in the Era of Precision Medicine: Where Are We Now? Evidence-Based Systemic Treatment Options and Future Cluster Oriented Perspectives

“…Noteworthy, responders included SDHB -mutant patients [ 66 , 70 , 71 ]. This is in accordance with the results of preclinical studies on human PPGL primary cultures that showed significantly stronger efficacy of cabozantinib in cluster 1 tumors, particularly SDHB-mutated, compared with cluster 2 tumors [ 66 , 72 ].…”

Paraganglioma of the anterior superior mediastinum: Presentation of a case of mistaken diagnosis so long and review of the literature

“…When the patient's clinical course and physical condition are intolerable, radionuclide therapy alone, a combination approach with pre-operative embolization or stereotactic body radiotherapy may be used [10] , [11] , [12] . Some novel molecular-targeted drugs include cabozantinib, selpercatinib, everolimus, sunitinib, alpelisib, trametinib, niraparib, and entinostat could be effective treatment options [13] , [14] .…”

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

“…In fact, they can be easily standardized, and yet, they provide enough complexity, such as 3D geometry, to represent relevant aspects of human tumours [ 38 ]. Spheroids generation facilitates the growth of highly uniform spheroids and allow real-time monitoring of drug-induced changes in their phenotypes [ 27 , 39 , 40 ]. We previously demonstrated that TME, represented by primary CAFs, plays a fundamental and specific role in inducing the invasion properties of spheroid cells and that this effect is extraordinarily enhanced in MTT SDHB sil ones [ 27 ].…”