Abstract
Inactivating mutations of the succinate dehydrogenase subunit B ( SDHB) gene and the subsequent stabilization and activation of the hypoxia-inducible factor 2-alpha (HIF2α) unit are recognized hallmarks associated with the development of metastatic pheochromocytomas and paragangliomas (MPPG). Despite this discovery, the development of systemic therapies for patients with MPPG has been very slow. The rarity of the disease, the lack of preclinical animal models, and the impracticable development of large clinical trials has hindered the therapeutic progress for MPPG. Chemotherapy and low-specific activity 131meta-iodo-benzyl-guanidine (MIBG) (manufactured by simple isotope exchange methodology) led to positive clinical responses in about a third of patients. Molecular targeted therapies were introduced into oncological clinical practice at the beginning of the 21st century. These therapies have been demonstrated to be effective for patients with cancers that previously exhibited limited responses to systemic chemotherapy, such as kidney and thyroid carcinomas and pancreatic neuroendocrine tumors. The pathogenesis of MPPG overlaps in some way with the pathogenesis of kidney, medullary thyroid, and pancreatic neuroendocrine carcinomas, providing scientific support to explore molecular targeted therapies such as tyrosine kinase and HIF inhibitors.
Highlights
Pheochromocytomas and paragangliomas (PPG) are rare neuroendocrine tumors originating in the paraganglia
Observations derived from phase II clinical trials with tyrosine kinase and hypoxia-inducible factors (HIFs) inhibitors have revealed anti-neoplastic effects
It is important to recognize that metastatic pheochromocytomas and paragangliomas (MPPG) are more challenging to treat when compared with other oncological conditions that are treated with these medications
Summary
Pheochromocytomas and paragangliomas (PPG) are rare neuroendocrine tumors originating in the paraganglia. Tyrosine kinase inhibitors and cardiovascular events in patients with MPPG Preliminary results of several clinical trials show that several TKIs with mainly anti-angiogenic activity may cause anti-tumor effects in a substantial number of patients with MPPG31,34. As suggested by the preliminary results of the cabozantinib phase II study, it is always better to choose a starting dose that is clearly associated with clinical benefits and that allows dose titration down, preserving effectiveness This approach may allow one to later titrate the dose up once an anti-tumor effect is achieved, as catecholamine secretion may have already decreased . The final results of the phase II clinical trial with high-specific activity MIBG (Azedra®) for MPPG that express the cell membrane catecholamineuptake transporter are impressive; more than 90% of patients exhibit clinical benefits[59] This medication has received breakthrough therapy designation by the FDA, and the clinical results are currently under evaluation by this regulatory agency. As the focus of this article is on tyrosine kinase and HIF2α inhibitors, we will not discuss these therapies further
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