Related Experiment Video
Updated: Feb 27, 2026
Author Spotlight: Exploring the Role of Ion Channels in Cancer: Characterization and Potential Treatment Approaches
Published on: June 16, 2023
New HIF2α inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas
1Division of Hematology and Medical OncologyDepartment of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, USA toledorodrigo79@gmail.com.
Abstract:
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 (HIF2α). 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-Lindau (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 HIF2α itself: EPAS1HIF2α 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 HIF2α activation in human cancer. The now available therapeutic opportunity to successfully inhibit HIF2α 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 HIF2α amino acids 529-532 (in PPGLs) and amino acids 533-540 (in erythrocytosis type 4), as well as against HIF2α protein activated by VHL, SDHx and FH mutations in PPGL-derived chromatin cells.
Insights
New inhibitors targeting hypoxia-inducible factor 2-alpha (HIF2α) show promise for clear cell renal cell carcinoma (ccRCC) and endocrine tumors. These drugs offer hope for patients with limited treatment options, including those with SDHB-related metastatic pheochromocytomas and paragangliomas.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) and endocrine neoplasias like pheochromocytomas and paragangliomas (PPGLs) share molecular drivers, particularly those stabilizing hypoxia-inducible factors (HIFs).
- Mutations in genes such as von Hippel-Lindau (VHL), succinate dehydrogenase (SDHx), fumarate hydratase (FH), transcription elongation factor B subunit 1 (TCEB1), and EPAS1 (encoding HIF2α) are implicated in HIF stabilization and cancer development.
- The direct activation of HIF2α by EPAS1 mutations has been identified as a novel oncogenic mechanism in human cancers.
Purpose of the Study:
- To highlight the therapeutic potential of novel hypoxia-inducible factor 2-alpha (HIF2α) inhibitors.
- To discuss the shared molecular pathways between ccRCC and PPGLs involving HIF stabilization.
- To explore the implications of HIF2α inhibition for treating various cancers, including rare endocrine tumors.
Main Methods:
- Review of recent independent studies on HIF2α inhibitors in ccRCC cell lines and xenograft models.
- Analysis of clinical data from a ccRCC patient treated with HIF2α inhibitors.
- Examination of genetic mutations (VHL, SDHx, FH, TCEB1, EPAS1) associated with HIF stabilization in ccRCC and PPGLs.
Main Results:
- Robust responses observed in ccRCC models and a patient treated with HIF2α inhibitors (PT2385 and PT2399).
- Identification of EPAS1 mutations in PPGLs, confirming a direct HIF2α activation mechanism.
- Potential for HIF2α inhibitors to treat cancers with specific genetic drivers, including SDHB-related metastatic PPGL.
Conclusions:
- Pharmacological inhibition of HIF2α represents a promising therapeutic strategy for ccRCC and potentially other cancers.
- Understanding shared molecular drivers like HIF stabilization opens avenues for treating rare endocrine tumors with limited options.
- Further investigation is warranted to determine the efficacy of HIF2α inhibitors against specific mutations in various cancer types.
![Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F68356.jpg&w=3840&q=50)
Related Concept Videos
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
01:22Adrenergic Antagonists: Pharmacological Actions of ɑ-Receptor Blockers
α1-blockers: These drugs inhibit α1-adrenoceptors on smooth muscle cells, resulting in vasodilation. This vasodilation lowers blood pressure, making α1-blockers valuable in treating hypertension. Additionally,...
01:18Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...
01:17Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers
Nonselective α-blockers: Nonselective α-blockers contain haloalkylamine or imidazoline...