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.

The fungal disease Valley fever causes a significant medical and financial burden for affected people in the endemic region, and this burden is on the rise. Despite the medical importance of this disease, little is known about ecological factors that influence the geographic point sources of high abundance of the pathogens Coccidioides posadasii and C. immitis, such as competition with co-occurring soil microbes. These “hot spots”, for instance, those in southern Arizona, are areas in which humans are at greater risk of being infected with the fungus due to consistent exposure. The aim of this study was to isolate native microbes from soils collected from Tucson, Arizona (endemic area for C. posadasii) and characterize their relationship (antagonistic, synergistic, or neutral) to the fungal pathogen with in vitro challenge assays. Secreted metabolites from the microbes were extracted and described using analytical techniques including high-performance liquid chromatography (HPLC) and mass spectrometry. Bacteria belonging to the genus Bacillus and fungi in the Fennellomyces and Ovatospora genera were shown to significantly decrease the growth of Coccidioides spp. In vitro. In contrast, other bacteria in the Brevibacillus genus, as well as one species of Bacillus bacteria, were shown to promote growth of Coccidioides when directly challenged. The metabolites secreted from the antagonistic bacteria were described using HPLC and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The microbes identified in this study as antagonists to Coccidioides and/or the metabolites they secrete have the potential to be used as natural biocontrol agents to limit the amount of fungal burden at geographic point sources, and therefore limit the potential for human infection.