The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

Von Hippel-Lindau Syndrome: Medical Syndrome or Surgical Syndrome? A Surgical Perspective

“…Several TKIs including sunitinib, cabozantinib, axitinib, lenvatinib, and pazopanib are currently being evaluated in phase II clinical trials. These therapies work by inhibiting cancer cell proliferation, metastasis, and the development of therapeutic resistance by suppressing tyrosine kinase receptors ( 36 ). Recently, studies were investigated on belzutifan, development code: MK-6482, which is a hypoxia-inducible factor-2α (HIF-2α) inhibitor for the treatment of adult patients with Hippel-Lindau syndrome.…”

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

“…Somatic mutations, germline mutations, and SNPs in EPAS1 are associated with tumorigenesis and polycythemia, a rare disease connected to certain malignancies [ 169 ]. The ClinVar database contains over 179 mutations within EPAS1 , while HIF-1α only has 32 mutations identified [ 170 ].…”

Special situations in pheochromocytomas and paragangliomas: pregnancy, metastatic disease, and cyanotic congenital heart diseases

“…Chemotherapy regimens are considered in patients with rapid tumour progression or absence of avidity in functional imaging. • Targeted therapies: Based on the identification of prevalent mutations in VHL/HIF axis that promote a dysregulation in angiogenesis and metabolism promoting tumorigenesis and aggressiveness through epithelial-mesenchymal transition, the development of VEGFR-targeted agents have been under research for the last years [62]. Sunitinib has been broadly studied based on the preclinical promising data in tumour growth control and hormone release.…”