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

F1000Res. 2018 Jul 30:7:F1000 Faculty Rev-1148. doi: 10.12688/f1000research.13995.1. eCollection 2018.


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.

Keywords: HIF inhibitors; Metastatic Pheochromocytoma; Metastatic paraganglioma; tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenal Gland Neoplasms / drug therapy*
  • Adrenal Gland Neoplasms / physiopathology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
  • Humans
  • Paraganglioma / drug therapy*
  • Paraganglioma / physiopathology
  • Pheochromocytoma / drug therapy*
  • Pheochromocytoma / physiopathology
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*


  • Basic Helix-Loop-Helix Transcription Factors
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases

Grants and funding

Rodrigo Toledo is a Miguel Servet-I Investigator (Institute of Health Carlos III) and is supported by a Fundación Olga Torres Emergent Researcher Grant. Rodrigo Toledo and Camilo Jimenez have received financial research support by a Paradifference Foundation Research Grant.