New HIF2α inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas

  1. Rodrigo Almeida Toledo*
  1. Division of Hematology and Medical Oncology, Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, USA
  1. Correspondence should be addressed to R A Toledo; Email: toledorodrigo79{at}
  1. Figure 1

    Activation of HIF2α by frequent somatic mutations in the VHL gene is the hallmark of clear cell renal cell carcinoma (ccRCC). VHL is also a major PPGL susceptibility gene. In addition to VHL, mutations in SDHx, FH and MET genes are also shared by both ccRCC and PPGLs. According to the results of tumor profiling studies, VHL-mutated ccRCCs and EPAS1 (HIF2α)-mutated PPGLs present elevated levels of the HIF2α target genes VEGFA, CCND1 and GLUT1, which are involved in angiogenesis, the cell cycle and cell metabolism. Newly developed HIF2α antagonists downregulate the expression of these cancer-related genes in ccRCC 786-0 VHL-null cell lines and in 786-0 xenograft tumors (Chen et al. 2016, Cho et al. 2016). A full color version of this figure is available at

  2. Figure 2

    Mutations in the EPAS1 HIF2α gene occur in the ODD domain. Mutations reported in pheochromocytomas and paragangliomas are depicted in black, mutations reported in familial erythrocytosis (type 4, OMIM 611783) are depicted in red and common polymorphisms detected at a high frequency in healthy controls are depicted in blue. Circles illustrate mutations that have been shown or are likely to be pathogenic, triangles indicate variants with an unknown clinical significance (VUS) and squares indicate common polymorphisms. Structures, protein domains and regions of binding and dimerization of HIF2α and ARNT (HIF-B) are shown. A: PAS (Per-ARNT-Sim) A domain; B: PAS (Per-ARNT-Sim) B domain. bHLH, basic helix-loop-helix domain; HIF2α antagonist, PT2399 and PT2385 (peloton therapeutics); ODD, oxygen-dependent degradation domain; TAD, transactivation domain. A full color version of this figure is available at

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