Development of drugs targeting hypoxia‐inducible factor against tumor cells with VHL mutation: Story of 127 years

Abstract

Intratumoral hypoxia is associated with tumor progression and therapeutic resistance. The VHL tumor suppressor gene was identified in 1993, and later studies revealed that the gene product pVHL interacts with other proteins to form the VBC complex. The VBC complex functions as an E3 ubiquitin ligase and regulates the abundance of the α‐subunit of the transcription factor hypoxia‐inducible factor (HIF). Hypoxia‐inducible factor regulates thousands of genes required for cells to adapt and survive in hypoxic conditions, and thus pVHL plays a major role in oxygen‐sensing pathways. Patients with von Hippel–Lindau (VHL) disease, harboring a germline mutation of the VHL gene, develop renal cell carcinomas and a series of tumors showing hypervascular phenotypes. The extensive findings that have clarified the function of VHL have contributed to the development of novel first‐in‐human drugs, including belzutifan, a HIF‐2α inhibitor. The 2019 Nobel Prize in Physiology or Medicine was awarded to Dr. William G. Kaelin Jr., Dr. Peter J. Ratcliffe, and Dr. Gregg L. Semenza as researchers contributing to clarifying the mechanism of the oxygen‐sensing pathway of cells. The first report of VHL disease was in 1894, meaning the development of a specific drug for this disease took almost 125 years. In this article, we describe how researchers and clinician scientists successfully clarified the function of VHL and achieved a preclinical proof of concept to apply for clinical trials, key requirements for drug development.

RNA-Based Strategies for Cancer Therapy: In Silico Design and Evaluation of ASOs for Targeted Exon Skipping

“…Similarly, the inactivation of the tumor suppressor VHL is a major genetic driver of both hereditary and sporadic renal cell carcinoma [61]. Although VHL-defective cancers can be targeted with clinical success by inhibiting its downstream effector HIF1a or VEGF-driven angiogenesis [62], we hypothesize that VHL function could be restored, at least in part, through ASO-mediated transcript modification. The comprehensive in silico approach successfully identified the highest-scoring exon for each gene and designed corresponding ASO sequences to induce its exclusion.…”

Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation

“…There are multiple drugs that can promote the degradation of its protein: HSP90 inhibitors (e.g., 17-allylamino-17-demethoxygeldanamycin), class II histone deacetylase (HDAC) inhibitors and the thioredoxin inhibitor (e.g., PX-12), which cause ubiquitination and the proteasomal degradation of HIF-1α. In particular, panobinostat is an inhibitor of histone deacetylase, which obstructs the HSP90/HDAC6 complex that interrelates with HIF-1α and hinders its degradation, hence preventing formation of the complex prompt degradation of HIF-1α [ 5 , 10 , 36 , 93 ]. Additionally, some antioxidants (e.g., ascorbate–vitamin C and N-acetyl cysteine) could be used to block tumor growth by inducing HIF-1α degradation.…”

“…The targeting of HIFs has been recognized as a prospective strategy for enhancing cancer therapies [ 8 , 9 , 10 ]. A number of small molecular inhibitors targeting HIF have been developed and incorporated into various drug delivery systems.…”

Radiogenomics and Texture Analysis to Detect von Hippel–Lindau (VHL) Mutation in Clear Cell Renal Cell Carcinoma

“…Individuals affected by VHL disease, possessing a germline mutation of the VHL gene, manifest renal cell carcinomas and a series of tumors displaying hypervascular characteristics. Comprehensive research elucidating VHL's function has contributed to pioneering first-in-human drugs, such as belzutifan, an HIF-2α inhibitor [46].…”