Proteostasis Modulation in Germline Missense von Hippel Lindau Disease.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
13 06 2023
13 06 2023
Historique:
received:
29
11
2022
revised:
06
02
2023
accepted:
03
04
2023
medline:
14
6
2023
pubmed:
6
4
2023
entrez:
5
4
2023
Statut:
ppublish
Résumé
Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
Identifiants
pubmed: 37018064
pii: 725139
doi: 10.1158/1078-0432.CCR-22-3651
pmc: PMC10330138
mid: NIHMS1891298
doi:
Substances chimiques
Vorinostat
58IFB293JI
Von Hippel-Lindau Tumor Suppressor Protein
EC 2.3.2.27
Biological Products
0
Banques de données
ClinicalTrials.gov
['NCT02108002']
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2199-2209Subventions
Organisme : Intramural NIH HHS
ID : ZIA NS003053
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA NS003132
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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