Exploiting cell fate transition to overcome radiation resistance in glioblastoma

PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor that affects about 15,000 Americans every year. Despite maximal surgical resection and chemoradiation, GBMs remain incurable. GBMs are notoriously radiation resistant. Molecular subtyping of GBMs by genomic analyses of patient tumors identified three major subtypes, termed Proneural (PN), Classical or Mesenchymal (MES), based on gene expression patterns. Collaborative efforts between the Sulman and Bhat laboratories over the years has uncovered glioma stem-like cells (GSCs) closely resembling molecular subtypes of GBM. These states, however, exhibit plasticity and we pioneered the notion of PN to MES transition based on studies using patient derived GSCs linking MES signatures with radio- resistance and identifying master transcription factors associated with the MES subtype. New exciting preliminary data from our laboratories have identified three independent molecular targets associated with radiation resistance. Using whole-genome CRISPR screens to identify gene targets associated with enhanced radiation sensitivity as well as and mass spectrometric evaluation of radiation induced protein complexes, we have uncovered three players involved in metabolic, epigenetic and DNA repair pathways that can be targeted to overcome radiation resistance in GSCs. The overall goal of this proposal is to combine these druggable targets with the standard use of fractionated photon radiation therapy (RT) and convert GSCs from radioresistant to radiosensitive. In Aim 1, we will examine if inhibition of N-acylneuraminate-9-phosphatase (NANP) will lead to radiosensitization of GBM transitioning from MES to PN states via metabolic reprogramming. In Aim 2, we will test if targeting High Mobility Group Box-2 (HMGB2) leads to a block of MES transitioning and alterations of chromatin and if it is lethal in combination with radiation. Finally, in Aim 3, we will examine the radiosensitizing effects of neuronal differentiation with combined TAZ inhibitors and ionizing radiation in pre-clinical models of GBM. Our proposal is significant because this is the first comprehensive study to examine the radiosensitizing effects of cell state transition blockade in GBM. Data generated from this grant will encompass TCGA datasets, patient derived GSCs, clinically relevant xenograft models as well as testing of inhibitors in these models with a trajectory toward Phase I clinical trials to overcome radioresistance in patients with GBM.