Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome

Junne Kamihara; Kayla V Hamilton; Jessica A Pollard; Catherine M Clinton; Jill A Madden; Jasmine Lin; Alma Imamovic; Catherine B Wall; Ari J Wassner; Brent R Weil; Matthew M Heeney; Sara O Vargas; William G Kaelin Jr; Katherine A Janeway; Rodolfo F Perini; Naseem J Zojwalla; Stephan D Voss; Steven G DuBois

doi:10.1056/NEJMoa2110051

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome

N Engl J Med. 2021 Nov 25;385(22):2059-2065. doi: 10.1056/NEJMoa2110051.

Authors

Junne Kamihara¹, Kayla V Hamilton¹, Jessica A Pollard¹, Catherine M Clinton¹, Jill A Madden¹, Jasmine Lin¹, Alma Imamovic¹, Catherine B Wall¹, Ari J Wassner¹, Brent R Weil¹, Matthew M Heeney¹, Sara O Vargas¹, William G Kaelin Jr¹, Katherine A Janeway¹, Rodolfo F Perini¹, Naseem J Zojwalla¹, Stephan D Voss¹, Steven G DuBois¹

Affiliation

¹ From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

Abstract

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adrenal Gland Neoplasms / drug therapy*
Adrenal Gland Neoplasms / genetics
Adrenal Glands / diagnostic imaging
Adrenal Glands / drug effects
Adrenal Glands / pathology
Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
Basic Helix-Loop-Helix Transcription Factors / genetics
Biomarkers / blood
Chromogranins / blood
Female
Gain of Function Mutation
Humans
Indenes / adverse effects
Indenes / therapeutic use*
Magnetic Resonance Imaging
Normetanephrine / blood
Paraganglioma / drug therapy*
Paraganglioma / genetics
Polycythemia / drug therapy*
Polycythemia / genetics
Signal Transduction
Syndrome
Whole Genome Sequencing

Substances

Basic Helix-Loop-Helix Transcription Factors
Biomarkers
Chromogranins
Indenes
Normetanephrine
endothelial PAS domain-containing protein 1
belzutifan

Grants and funding

R35 CA210068/CA/NCI NIH HHS/United States