Gene expression signatures of paragangliomas and pheochromocytomas (PPGLs) reveal two main clusters where tumors with SHDx and VHL mutations belong to a cluster which has a gene signature associated with hypoxic signaling or pseudohypoxia. Mutations in either VHL or SDH genes lead to the stabilization of hypoxia-inducible factor 1a and 2a (HIF-1a and HIF-2a) and occasionally, HIF2A/EPAS1 is activated through a mutation in the VHL-recognition amino acid. Recently, a selective HIF-2 inhibitor, PT2385 was reported. PT2385 binds to a HIF-2a unique protein pocket in the PAS-B domain, and thus, prevents the HIF-2a-ARNT dimerization and the formation of an active HIF-2 transcription complex. We synthesized PT2385 and evaluated its effect(s) on clear cell renal carcinoma cells (ccRCC) and neuroblastoma cells, cell types with an active HIF-2 at normoxic or hypoxic conditions. While PT2385 inhibited the expression of HIF-2 driven genes like VEGF in HIF-2a expressing CCRCC cells with lost VHL and HIF1A expression, VHL mutated ccRCC cells with intact HIF1A and HIF2A did not respond equally well to PT2385 treatment. Neuroblastoma PDX-derived cell lines with high HIF-2a expression at normoxia as well as serum-cultured established cell lines with hypoxia-stabilized HIF-2a did not respond to PT2385 by down-regulation of HIF-2 driven genes like VEGF. In contrast, siHIF2A, which knocks down HIF-2a expression, diminishes the expression of HIF-2 down-stream target genes. Putative models explaining our data will be discussed. We will also report our ongoing efforts to establish orthotopic human PPGL-PDXs and describe the network of clinicians we collaborate with to get relevant tumor tissue for these studies.