DDDR-69. Discovery, validation and deployment of a molecular signature of vulnerability to GB13 in an early stage GBM clinical trial

Abstract Progress in FDA approval of new drugs for glioblastoma (GBM) faces an uphill path, confounded by anatomic obstacles (blood brain barrier), exceptionally heterogeneous tumor populations within and across patients, and innate resistance mechanisms. Expression of a target to targeted therapy is also inadequate to accurately predict efficacy. We undertook molecular profiling across cultures of GBM PDX models which displayed a near 100x differential vulnerability to a toxin-conjugated ligand (GB13) addressing IL13Ra2. This recombinant protein is a modified form of IL13 with a near-1,000x higher affinity to IL13Ra2 compared to IL13Ra1. The toxin (pseudomonas exotoxin, PE) has likewise been modified to not bind to canonical receptors, affording highly specific targeting of GB13 to the intended tumor cells. While transduction of IL13Ra2 in glioma cells affords heightened activity of GB13 (5-15x) compared to cognate cells without, additional mechanisms of toxin activation or inactivation may account for the wide range of vulnerability seen across glioma cells with comparable endogenous IL13Ra2 expression. Differential gene expression analysis comparing sensitive vs resistant GBM PDX models uncovered significant elevation of golgi-to-endoplasmic reticulum retro-trafficking and transport pathways in sensitive cells. This nominal housekeeping function for recycling cargo-encapsulated vesicle movement for intracellular and extracellular communication proves to be vulnerable to cell functional states of stress, reactive oxygen, metabolic fluxes, and ageing, in some cases driven by post-translational modifications of key carrier proteins. The size of GB13 (79kDa) warrants direct intracranial convection enhanced delivery (CED), further contributing to minimal systemic exposure while maximally addressing the tumor field. Parameters of delivery volume, catheter placement, and subsequent assessment of drug distribution, as well as induced cell death related to abundance of IL13Ra2 expression and genes driving golgi-to-ER retrograde traffic / transport will be analyzed for prediction of response in this early stage trial as part of the NCI Glioblastoma Therapeutics Network.