Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors

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.

‘Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta‐analysis’

“…Few studies have tried to exploit the underlying molecular mechanisms viz. mutation in succinate dehydrogenase subunit B gene (SDHB) and activation of hypoxia‐inducible factor HIF2α and evaluated the role of tyrosine kinase inhibitors (TKIs) . The results so far have been mixed with a reported 57% response rate in case of Sunitinib which was, however, accompanied by a significant proportion of adverse effects and treatment discontinuation .…”

“…The results so far have been mixed with a reported 57% response rate in case of Sunitinib which was, however, accompanied by a significant proportion of adverse effects and treatment discontinuation . New generation TKIs like cabozantinib are expected to cause lesser adverse effects but need to be investigated further . In this setting, an equivalent therapeutic efficacy coupled with better safety profile and quality of life could favour the use of PRRT over chemotherapy and I‐ 131 MIBG in advanced PPGLs.…”

“…While these modalities have shown favourable albeit modest response with respect to tumour volume, data on survival benefit are scarce . Further, chemotherapy and I‐131 MIBG (I‐ 131 MIBG) are also associated with significant toxicity . In such a scenario, there is a need for clinically effective and safer treatment options for the management of advanced PPGLs.…”

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…Several TKI's that been described in case reports, series or phase II trials, such as sunitinib, cabozantinib, lenvatinib, pazopanib, and axitinib. An excellent overview of existing data and forthcoming trials was recently published by Toledo and Jiminez . All TKIs inhibit angiogenesis, by inhibiting the activation of the VEGF receptor (VEGFR).…”

Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma

“…As a result, HIF inhibitors could be a potential therapy for patients with cluster I PHEO/PGL. Molecular studies have identified HIF-2α as one of the main oncogenic drivers of PHEOs/PGLs [44,[54][55][56].…”