Background: Presurgical treatment with an alpha-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced alpha-adrenergic receptor mediated vasoconstriction in patients... Show moreBackground: Presurgical treatment with an alpha-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced alpha-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in alpha-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the alpha 1A, alpha 1B, alpha 1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and alpha 2A, alpha 2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of alpha-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of alpha-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to alpha-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations. Show less
This review describes human and rodent-derived cell lines and xenografts developed over the last five decades that are suitable or potentially suitable models for paraganglioma-pheochromocytoma... Show moreThis review describes human and rodent-derived cell lines and xenografts developed over the last five decades that are suitable or potentially suitable models for paraganglioma-pheochromocytoma research. We outline the strengths and weaknesses of various models and emphasize the recurring theme that, despite the major challenges involved, more effort is required in the search for valid human and animal cell models of paraganglioma-pheochromocytoma, particularly those relevant to cancers carrying a mutation in one of the succinate dehydrogenase genes. Despite many setbacks, the recent development of a potentially important new model, the RSO cell line, gives reason for optimism regarding the future of models in the paraganglioma-pheochromocytoma field. We also note that classic approaches to cell line derivation such as SV40-mediated immortalization and newer approaches such as organoid culture or iPSCs have been insufficiently explored. As many existing cell lines have been poorly characterized, we provide recommendations for reporting of paraganglioma and pheochromocytoma cell lines, including the strong recommendation that cell lines are made widely available via the ATCC or a similar cell repository. Basic research in paraganglioma-pheochromocytoma is currently transition ing from the analysis of genetics to the analysis of disease mechanisms and the clinically exploitable vulnerabilities of tumors. A successful transition will require many more disease-relevant human and animal models to ensure continuing progress. Show less
Purpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The... Show morePurpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-131-MIBG, Y-90 and Lu-177-DOTATATE), chemotherapy and targeted therapy. Recent findings The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed. Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype. Show less
Berkel, A. van; Vriens, D.; Visser, E.P.; Janssen, M.J.R.; Gotthardt, M.; Hermus, A.R.M.M.; ... ; Timmers, H.J.L.M. 2019
Eijkelenkamp, K.; Olderode-Berends, M.J.W.; Luijt, R.B. van der; Robledo, M.; Dooren, M. van; Feelders, R.A.; ... ; Horst-Schrivers, A.N.A. van der 2018
