THE INTEGRATED STRESS RESPONSE IN GBM PATHOGENESIS AND RESPONSE TO THERAPY

About This Grant

Abstract The ability of tumor cells to adapt and survive endogenous and environmental stress is essential for tumor initiation and development. Glioblastoma (GBM) is the most malignant brain tumor, with high mortality and resistance to therapy. Within the heterogeneous GBM tumors, a highly tumorigenic subpopulation of Glioma Stem Cells (GSCs) drives tumor growth and promotes recurrence. GSCs can survive and proliferate in a relatively hostile tumor microenvironment, which triggers adaptive stress response mechanisms to restore protein homeostasis and promote tumor cell survival under abnormal conditions. Most forms of stress converge on one signaling pathway termed the integrated stress response (ISR), which signals through phosphorylating eIF2α (p-eIF2α; eukaryotic translation initiation factor 2α). Activation of the ISR causes a temporary shutdown of global protein translation and selective translation of cytoprotective transcripts. However, under prolonged stress, p-eIF2α promotes apoptosis. p-eIF2α halts protein synthesis by inhibiting eIF2B, which plays a key role in regulating mRNA translation and balancing the pro- and anti-survival effects of p-eIF2α. Our studies revealed a direct link between ISR signaling and response to several GBM therapeutics. Our central hypothesis is that the interplay between p-eIF2α and eIF2B determines therapeutic sensitivity and translation potential that drives tumor growth. We propose that while high levels of ISR effectively block global protein translation, mild ISR signaling, such as one caused by therapy, reprograms translation and selectively enhances the translation of a subset of mRNAs to confer cytoprotection and promote survival. To test our hypotheses and to address how conventional GBM therapies or the abnormal tumor microenvironment supports tumor progression and confers therapeutic resistance, we propose to carry out the following aims: Aim 1. Defining the role of eIF2B in translational regulation, tumor growth, and therapy response. Aim 2. Investigating the role and mechanism of translational reprogramming in GBM therapy response. Aim 3. Selective Targeting of aminoacyl-tRNA synthetases to enhance the efficacy of GBM Therapies. The proposed work will determine whether modulating the ISR could impair tumor growth and increase the efficacy of targeted therapeutics currently used in the clinic. Cell culture or in silico models cannot closely mimic the tumor environment, compounds pharmacokinetics and brain penetrance of small molecules, therefore the use of animals is warranted in our study.