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HIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions

  • Sri Harsha Tella
    Affiliations
    Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, MD 20892-1109, USA
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  • David Taïeb
    Affiliations
    Biophysics and Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Aix-Marseille University, 264, Rue Saint-Pierre, 13385 Marseille, France
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  • Karel Pacak
    Correspondence
    Corresponding author: Section on Medical Neuroendocrinology, Developmental Endocrine Oncology and Genetics Affinity Group, Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, MD 20892-1109, USA. Fax: +1 (301) 402 4712.
    Affiliations
    Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, MD 20892-1109, USA
    Search for articles by this author
Published:September 22, 2017DOI:https://doi.org/10.1016/j.ejca.2017.08.023

      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)
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