sildenafil citrate + sorafenib tosylate + valproic acid

This is an investigational combination therapy consisting of three small molecule drugs—sildenafil citrate, sorafenib tosylate, and valproic acid—administered together for the treatment of recurrent high-grade glioma. - **Sildenafil citrate** is a phosphodiesterase type 5 (PDE5) inhibitor primarily used for erectile dysfunction and pulmonary hypertension; it increases intracellular cGMP by inhibiting its breakdown. - **Sorafenib tosylate** is a multikinase inhibitor that targets several tyrosine kinases involved in tumor cell proliferation and angiogenesis, including RAF kinases, vascular endothelial growth factor receptors (VEGFR), and platelet-derived growth factor receptor alpha (PDGFRα). - **Valproic acid** is a fatty acid derivative anticonvulsant with histone deacetylase inhibitory activity; it modulates gene expression and has antitumor properties. In phase 2 clinical trials (NCT01817751), this combination demonstrated clinical activity in patients with recurrent high-grade glioma, showing median progression-free survival of approximately 3.7 months and median overall survival of about 10 months[1][2][3][4]. The regimen was generally well tolerated with mostly grade 1–2 toxicities[1][2]. The trial also found that low expression levels of the chaperone protein GRP78 were associated with improved overall survival[1][2].