Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
Clin Cancer Res. 2023 Jun 13;29(12):2199-2209. doi: 10.1158/1078-0432.CCR-22-3651.
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.
错义突变的 von Hippel Lindau（VHL）蛋白（pVHL）保持内在功能，但在 VHL 疾病中发生蛋白酶体降解和肿瘤起始和/或进展。伏立诺他可以挽救错义突变的 pVHL 并在临床前模型中阻止肿瘤生长。我们询问短期口服伏立诺他是否可以挽救胚系错义 VHL 患者中枢神经系统血管母细胞瘤中的 pVHL。
我们给 7 名受试者（年龄 46.0±14.5 岁）口服伏立诺他，然后通过手术切除有症状的血管母细胞瘤（ClinicalTrials.gov 标识符 NCT02108002）。
所有患者均耐受伏立诺他，无严重不良事件。与来自同一患者的未治疗血管母细胞瘤相比，肿瘤性基质细胞中 pVHL 的表达升高。我们发现下游低氧诱导因子（HIF）效应物的转录抑制。在机制上，伏立诺他在体外防止 Hsp90 募集到突变的 pVHL。伏立诺他对 Hsp90-pVHL 相互作用、pVHL 挽救和下游 HIF 效应物转录抑制的作用独立于 VHL 基因座错义突变的位置。我们通过单核转录组谱分析证实了抑制促肿瘤途径的肿瘤性基质细胞特异性效应。
我们发现，在胚系错义 VHL 突变的患者中，口服伏立诺他治疗具有很强的生物学效应，值得进一步临床研究。这些结果为使用蛋白质稳态调节治疗涉及蛋白质错误折叠的综合征性实体瘤提供了生物学证据。伏立诺他的蛋白质稳态调节挽救了错义突变的 VHL 蛋白。需要进一步的临床试验来证明肿瘤生长的抑制。
