DIPG-68. FLAG-003, A NOVEL, DUAL-ACTION THERAPEUTIC, DEMONSTRATES IN-VITRO ACTIVITY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract

Abstract BACKGROUND FLAG-003 is a novel, rationally-designed, CNS-penetrant, dual-acting agent that inhibits receptor tyrosine kinase activity and microtubule polymerization. Preclinical studies in glioblastoma (GBM) demonstrated decreased cell viability, reduced tumor volumes, decreased microvessel density, and increased survival. Remarkably, using an orthotopic DIPG model, all mice treated with FLAG-003 at 275 mg/day/orally displayed tumor regression, tumor reduction and increased survival. Given the significant preclinical activity against DIPG, as well as the known heterogeneity of DIPG, we evaluated the efficacy of FLAG-003 in vitro against a panel of DIPG cell lines. METHODS Eight DIPG cell lines hosted at the Center for Patient Derived Models (CPDM) were selected based on genomic and growth characteristics. Cells were plated on 384-well plates; 24 hours after plating, cells were dosed with 1nM to 50uM (12 step log curve) FLAG-003. Three technical replicates were performed per step. Controls consisted of positive kill control Staurosporine, negative growth control of 0.5% DMSO, or no DMSO for baseline growth. ONC201, a small molecule antagonist of DRD2/3 currently in clinical trials for DIPG, was used as a comparator. We also evaluated two GBM patient-derived models. RESULTS FLAG-003 demonstrated efficacy in all DIPG and GBM cell lines tested with IC50 less than 100nM. FLAG-003 was more potent compared to ONC201 in all models evaluated. CONCLUSIONS Single agent FLAG-003 demonstrated activity against a panel of DIPG cell lines. As next steps, we are exploring the efficacy of this drug in orthotopic DIPG PDX models. Continued development of FLAG-003 as a potential therapeutic candidate for DIPG patients is warranted and underway.