GENT-11. SMALL MOLECULE EPIGENETIC SCREEN IDENTIFIES NOVEL EZH2 AND HDAC INHIBITORS THAT TARGET GLIOBLASTOMA BRAIN TUMOR-INITIATING CELLS

Abstract

OBJECTIVE: To determine whether glutamine (GLN), tryptophan (TRP), and tryptophan metabolite concentrations are higher in cerebralspinal fluid (CSF) dogs with naturally occurring portosystemic shunts (PSS), compared with control dogs. ANIMALS: 11 dogs with confirmed PSS and 12 control dogs fed low- and high-protein diets. PROCEDURE: Cerebrospinal fluid and blood samples were collected from all dogs. Serum and CSF concentrations of GLN, alanine, serine, TRP, 5-hydroxyindoleacetic acid (5-HIAA), and quinolinic acid (QUIN) were measured. RESULTS: Cerebrospinal fluid concentrations of GLN, TRP, and 5-HIAA were significantly higher in PSS dogs, compared with control dogs fed high- or low-protein diets. Cerebrospinal fluid QUIN concentration was significantly higher in PSS dogs, compared with control dogs fed the low-protein diet. Serum QUIN concentration was significantly lower in PSS dogs, compared with control dogs fed either high- or low-protein diets. CONCLUSIONS AND CLINICAL RELEVANCE: An increase in CNS GLN concentration is associated with high CSF concentrations of TRP and TRP metabolites in dogs with PSS. High CSF 5-HIAA concentrations indicate an increased flux of TRP through the CNS serotonin metabolic pathway, whereas high CSF QUIN concentrations indicate an increased metabolism of TRP through the indolamine-2,3-dioxygenase pathway. The high CSF QUIN concentrations in the face of low serum QUIN concentrations in dogs with PSS indicates that QUIN production from TRP is occurring in the CNS. High concentrations of QUIN and other TRP metabolites in the CNS may contribute to neurologic abnormalities found in dogs with PSS and hepatic encephalopathy.