{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:26:58Z","timestamp":1790483218495,"version":"4.1.0"},"reference-count":82,"publisher":"Bioscientifica","issue":"9","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Two recent independent studies published in Nature show robust responses of clear cell renal cell carcinoma (ccRCC) cell lines, preclinical ccRCC xenograft models and, remarkably, a patient with progressive ccRCC despite receiving multiple lines of treatment, to the long-awaited, recently developed inhibitors of hypoxia-inducible factor 2-alpha (HIF2\u03b1). This commentary published in Endocrine-Related Cancer is based on the recognition of similar molecular drivers in ccRCC and the endocrine neoplasias pheochromocytomas and paragangliomas (PPGLs), ultimately leading to stabilization of HIFs. HIF-stabilizing mutations have been detected in the von Hippel\u2013Lindau (VHL) gene, as well as in other genes, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH) and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF2\u03b1 itself: EPAS1HIF2\u03b1. Importantly, the recent discovery of EPAS1 mutations in PPGLs and the results of comprehensive in vitro and in vivo studies revealing their oncogenic roles characterized a hitherto unknown direct mechanism of HIF2\u03b1 activation in human cancer. The now available therapeutic opportunity to successfully inhibit HIF2\u03b1 pharmacologically with PT2385 and PT2399 will certainly spearhead a series of investigations in several types of cancers, including patients with SDHB-related metastatic PPGL for whom limited therapeutic options are currently available. Future studies will determine the efficacy of these promising drugs against the hotspot EPAS1 mutations affecting HIF2\u03b1 amino acids 529\u2013532 (in PPGLs) and amino acids 533\u2013540 (in erythrocytosis type 4), as well as against HIF2\u03b1 protein activated by VHL, SDHx and FH mutations in PPGL-derived chromatin cells.<\/jats:p>","DOI":"10.1530\/erc-16-0479","type":"journal-article","created":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T20:20:19Z","timestamp":1498854019000},"page":"C9-C19","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":35,"title":["New HIF2\u03b1 inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas"],"prefix":"10.1530","volume":"24","author":[{"given":"Rodrigo Almeida","family":"Toledo","sequence":"first","affiliation":[{"name":"Division of Hematology and Medical Oncology","department":["Department of Medicine, Cancer Therapy and Research Center, 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