STEM-11. TARGETING THE MYC-WDR5 AXIS TO SUPPRESS GLIOBLASTOMA GROWTH AND SELF-RENEWAL

Abstract Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by cancer stem cells (CSCs) that promote tumor growth, recurrence, and resistance to therapy. The transcription factor Myc, a master regulator of cellular growth and metabolism, is frequently dysregulated in GBM, making it a critical driver of tumorigenesis. Despite its importance, Myc has been a challenging therapeutic target due to its lack of accessible, druggable surfaces. Our group previously employed spatially resolved functional screening in GBM organoids to uncover WDR5, a chromatin regulator and critical binding partner of Myc, as critical in GBM CSC maintenance. We showed that disruption of WDR5 reduces H3K4me3-driven transcriptional activity at important stem cell genes including SOX2 and Myc. Notably, overexpression of Myc in isogenic transformed human Neural Stem Cells caused a ~100-fold increase in sensitivity to WDR5 inhibitor treatment. These findings suggest a bidirectional relationship, where WDR5 is not only essential for MYC activity, but MYC also establishes a dependency on sustained WDR5 function. We theorized that this induced non-oncogene addiction could be leveraged by targeting the WDR5-Myc interaction, opening an innovative approach to indirectly targeting Myc. Starting with MYC-box-IIIb peptide, which binds WDR5’s Myc-binding WBM site, we optimized precision-linked proteomimetic (PLP) molecules to target WDR5 with high affinity. We developed a novel PLP, G-8068, with multi-log potency enhancement over the starting peptide, attributed to multivalency. In GBM CSCs, G-8068 triggers WDR5 degradation and concomitant destabilization of Myc. Targeting this critical interaction surface, and the resulting simultaneous loss of both WDR5 and Myc, leads to loss of SOX2 stem cell marker expression and a dramatic loss of GBM CSC self-renewal and growth. G-8068 further disrupts GBM self-renewal in patient-derived organoids, including targeting of both hypoxic and normoxic CSC populations. The level of these effects was not achieved by small molecule WDR5 WIN-site inhibitors or their corresponding degraders.