Authors: Panagiotis Mastorakos, MD PhD; Jacqueline Boyle; Konstantinos Floros; Russell Lonser; Prashant Chittiboina (Bethesda, MD)

Introduction: Von Hippel-Lindau disease (VHL) is a tumor suppressor syndrome with a propensity for multiple central nervous system (CNS) hemangioblastomas. Current standard of care is surgical resection which is linked to significant morbidity and mortality. Normally, VHL protein (pVHL) marks hypoxia inducible factor 1a (HIF1a) for degradation by E3 ligase activity. In VHL disease, mutations lead to decreased pVHL activity, elevated HIF1a signaling, and tumorigenesis. With germline missense mutations, mutated pVHL retains activity, but is rapidly degraded via chaperonin (Hsp90) binding. Histone deacetylase inhibitors (HDACIs), such as Vorinostat, can restore pVHL levels by decreasing the affinity of Hsp90 to misfolded pVHL. In pre-clinical models, HDACI-mediated pVHL stabilization can significantly attenuate tumor growth. We aimed to determine whether vorinostat can safely reduce degradation of mutant VHL protein in VHL patients with germline missense mutations. Methods: We enrolled seven germline missense VHL patients with symptomatic CNS hemangioblastomas. The subjects received 400 mg of Vorinostat by mouth daily for seven days prior to surgery and subsequently underwent surgical resection. Tissue samples were analysed using qPCR, Western blot analysis and immunohistochemistry. Results: Vorinostat was well tolerated by all patients. pVHL levels in resected hemangioblastomas were significantly higher following Vorinostat administration compared to control specimens with no change in the mRNA levels. Conclusion: Vorinostat is well tolerated by patients with symptomatic CNS hemangioblastomas in the setting of germline missense VHL disease and results in stabilization of mutated pVHL protein. These results suggest that Vorinostat may be a promising treatment for patients with a missense germline mutation and constitute an example of how deep understanding of the pathogenesis of a disease can lead to development of personalized treatments.