Highlights
- •HIF stabilisation in tumorigenesis of pseudohypoxic paragangliomas and related tumours.
- •Similarities between pathogenesis of clear cell renal cancer and pseudohypoxic paraganglioma are discussed.
- •Concept of targeting HIF-2α pathway in pseudohypoxic subtype of paragangliomas is proposed.
Abstract
Paragangliomas (PGLs) belong to the most hereditary endocrine tumours. The existence
of mutated HIF2A in these tumours, the role of oncometabolites on HIFs stabilisation
and a recent concept proposing how hereditary PGLs converge on the hypoxia-signalling
pathway, brought solid evidence of the existence of PGL hypoxiom. Hypoxia-inducible
factor 2alpha (HIF-2α) antagonists -PT2385, and PT2399 have been shown to have promising
results in the management of clear cell renal cell carcinoma by targeting the HIF-2α
pathway in recent and ongoing clinical trials (PT2799). The main aim of this perspective
is to address the possibility of HIF-2α antagonists in the management of tumours,
beyond clear cell renal cell carcinoma, where the dysfunctional hypoxia-signalling
pathway, especially HIF-2α, referred here as the Achilles' heel, plays a unique role
in tumorigenesis and other disorders. These tumours or disorders include PGLs, somatostatinomas,
hemangioblastomas, gastrointestinal stromal tumours, pituitary tumours, leiomyomas/leiomyosarcomas,
polycythaemia and retinal abnormalities. We hope that HIF-2α antagonists are likely
to emerge as a potential effective treatment of choice for HIF-2α–related tumours
and disorders.
Keywords
Abbreviations:
SDHx (Succinate dehydrogenase complex), FH (Fumarate hydratase), MDH2 (Malate dehydrogenase 2), VHL (Von Hippel-Lindau), HIF2A (Hypoxia-inducible factor 2 alpha), PHD1 (Prolyl hydroxylase 1), PHD2 (Prolyl hydroxylase 2), DNA (Deoxyribonucleic acid), ARNT (Aryl hydrocarbon receptor nuclear translocator), VEGFA (Vascular endothelial growth factor A), GLUT1 (Glucose transporter 1), PAI-1 (Plasminogen activator inhibitor-1), CCND1 (Cyclin D1), Scgb3a1 (Secretoglobin Family 3A Member 1)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 22, 2017
Accepted:
August 29,
2017
Received:
August 26,
2017
Identification
Copyright
© 2017 Published by Elsevier Ltd.
