EXTH-09. HSP90 INHIBITION AS A NOVEL THERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor. The mean age of onset 7-9 years with a median survival 9 months following diagnosis. Histone 3 (H3) mutations (H3K27M) have been identified in approximately 80% patients, representing intriguing target, but how to do this unclear. To address this, we performed synthetic lethality drug screen over 2400 compounds on isogenic cells expressing H3K27M and empty vector. 37 drugs were synthetically lethal H3K27M, including HSP90 inhibitors. In cancer, has higher isoelectric point which can be targeted specifically by PU-H71. Using PU-H71, complexed oncogenic clients inhibited reduce tumor cell viability. We tested PU-H71 primary patient derived DIPG lines demonstrating caspase-3/7 mediated death within 24 hours (n=3) IC50 100-200 nM (n=5) at 72 hours. molecular chaperone that supports protein activation localization; thus, its inhibition may allow simultaneous targeting multiple pathways. determine pathways are used PU-H71-conjugated beads pull-down client proteins. LC-MS/MS characterization the interactome from three (SU-DIPG XVII, SU-DIPGXXV, SU-DIPG 50) 339 overlapping proteins MAPK3, SMS, SRM, CTSP1, OAT, GMPS, PYG. Pathway enrichment analysis highlighted roles cycle regulation metabolic processes. Treating successfully reduced viability poor penetration. overcome isoform developed, PU-HZ151, will test vivo efficacy for DIPG.