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Published on: September 7, 2021
Proteostasis Modulation in Germline Missense von Hippel Lindau Disease
Prashant Chittiboina1,2, Debjani Mandal1, Alejandro Bugarini1,3
1Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
Purpose:
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.
Patients And Methods:
We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002).
Results:
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.
Conclusions:
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.
Insights
Short-term oral vorinostat effectively rescues missense mutated von Hippel-Lindau (VHL) protein in patients with VHL disease. This proteostasis modulation shows promise for treating solid tumors caused by protein misfolding.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Missense mutations in the von Hippel-Lindau (VHL) protein (pVHL) lead to its degradation and contribute to tumor development in VHL disease.
- Preclinical studies show vorinostat can rescue mutated pVHL and inhibit tumor growth.
Purpose of the Study:
- To investigate if short-term oral vorinostat administration can rescue pVHL in patients with germline missense VHL mutations presenting with central nervous system hemangioblastomas.
Main Methods:
- Seven patients with germline missense VHL mutations received oral vorinostat before surgical removal of symptomatic hemangioblastomas.
- pVHL expression, HIF effector activity, and molecular mechanisms were analyzed.
Main Results:
- Vorinostat was well-tolerated, with no serious adverse events.
- Elevated pVHL expression was observed in neoplastic stromal cells post-treatment.
- Transcriptional suppression of hypoxia-inducible factor (HIF) effectors and inhibition of Hsp90 recruitment to mutated pVHL were confirmed.
- These effects were mutation-location independent and specific to neoplastic stromal cells.
Conclusions:
- Oral vorinostat demonstrates a significant biological effect in patients with germline missense VHL mutations.
- These findings support proteostasis modulation as a therapeutic strategy for syndromic solid tumors associated with protein misfolding.
- Further clinical trials are warranted to confirm tumor growth arrest.
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