EXTH-62. COMBINATIONAL TREATMENT OF G-QUADRUPLEX STABILIZER CX-5461 AND IONIZING RADIATION POTENTIATES SELECTIVE LETHALITY IN PRECLINICAL ATRX-DEFICIENT GLIOMA MODELS

• DOI: 10.1093/neuonc/noad179.0915
• Publication Date: 2023-11-11T23:21:01Z
• Authors: Sharvari Dharmaiah; Prit Benny Malgulwar; William E Johnson; Brandon A Chen; Ahsan S Farooqi; Jason Huse
• Keywords: ATRX; Synthetic Lethality

Abstract Mutations in α-thalassaemia/mental retardation X-linked (ATRX) are a critical molecular marker for fatal high-grade glioma (HGG). Standard of care has remained stagnant the last 30 years, with no therapies approved specifically ATRX-deficient glioma. ATRX mutations give rise to abnormal DNA secondary G-quadruplex (G4) structures at GC-rich regions genome, altering genome-wide accessibility chromatin and enhancing damage. We aim use G4 stabilizers, class novel small molecule compounds that selectively bind stabilize G4s, enhance damage induce cell death Using patient-derived stem cells (GSCs) stabilizing compound CX-5461 (Senhwa Biosciences), we evaluated efficacy stabilization as single agent combination ionizing radiation (IR). As IR is standard DNA-damaging, it may hold strong potential synergize CX-5461. Here, report GSCs demonstrate dose-sensitive lethality CX-5461, compared controls. Mechanistic studies reveal activates p53-independent apoptosis, exhibits G2/M arrest GSCs, upregulates G4s (BG4), replication stress (ATR, RPA32) (ATM, γH2AX) pathways GSCs. These functional findings corroborated by -intact GSC flank xenograft mouse models, which were separated into following treatment groups: 1) vehicle, 2) alone, 3) 4) (n = 20/group). Excitingly, combinational leads profound tumor growth delay exclusively tumors vehicle (p 0.0004), alone 0.0001), or 0.0002) groups. Multiplex immunohistochemistry shows enhanced induction stress, damage, recapitulating vitro findings. Taken together, our work defines mechanisms action therapeutic strategy pre-clinical HGG, implications clinical translation.