MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma.

Abstract

INTRODUCTION:

Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile.

AREAS COVERED:

This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered.

EXPERT OPINION:

Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.

• Authors: Elshad Hasanov, Eric Jonasch
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 30 Issue 5 Pg. 495-504 (May 2021) ISSN: 1744-7658 [Electronic] England
• PMID: 33945366 (Publication Type: Journal Article, Review)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• endothelial PAS domain-containing protein 1

Topics

• Administration, Oral
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors)
• Carcinoma, Renal Cell (drug therapy, etiology)
• Humans
• Kidney Neoplasms (drug therapy, etiology)
• Quality of Life
• von Hippel-Lindau Disease (complications, drug therapy)