Therapeutic Targeting in EGFR-amplified Glioblastoma

Therapeutic Targeting in EGFR-amplified Glioblastoma Glioblastomas (GBM) are common and the most malignant adult tumors in the central nervous system with a poor prognosis. Among IDH wild type (WT) GBM under the new 2021 WHO classification, >55% tumors have EGFR amplification and/or mutations which is an established oncogenic driver of GBM malignancy and has served as a biomarker and therapeutic target of high interest. However, EGFR- targeting therapies remain ineffective, clinically, for GBM treatment. The failures of targeting EGFR are largely attributed to GBM tumor heterogeneity with intertwined oncogenic signaling, dynamic switching between tumor subtypes, and an immuno-suppressive tumor microenvironment. While the canonical downstream signaling of EGFR is well understood, other non-canonical pathways remain to be discovered in order to take advantage of this prevalent oncogenic driver as a therapeutic target in GBM. The goal of this project is to explore new therapeutic approaches for EGFR-amplified GBM by assessing the role of a largely uncharacterized gene that is co-amplified with EGFR in GBM, EGFR long non-coding downstream RNA (ELDR). ELDR is the most up-regulated long non-coding RNA (lncRNA) in EGFR-amplified GBM where ELDR expression augments the tumorigenicity of GBM cells and does so independently of EGFR signaling. ELDR binds to the purine-rich element-binding protein alpha (PURA) that is tumor suppressive in GBM. ELDR-PURA binding prevents PURA from interacting with the proto-oncogene BMI1, thus disrupting the PURA-BMI1 association in GSCs, and in so doing should increase BMI1/PRC1 oncogenic activity. Importantly, nuclear ELDR is found enriched in the nuclear speckles (NS), a membrane-less subcellular structure and a biomolecular condensate critical in cancer progression and chemoresistance, and interacts with multiple proteins in the nucleus, mostly in NS, thus simultaneously modulating different signaling and cellular processes. In this project, we plan to determine how the ELDR-PURA association affects GBM biologic properties through affecting PURA-BMI1 interaction thereby regulating BMI1 activity, assess effects of NS-enriched ELDR on GBM biologic properties, and determine whether specific targeting of ELDR using antisense oligonucleotides (ASO), instead of inhibiting individual ELDR-effectors, enhances therapeutic responses of GBM. This project will be the first to study a consequence of the EGFR locus amplification in GBM through ELDR in GBM biology and therapeutic response. The results of this study will not only advance our understanding of the importance of lncRNA expression in cancer, which has the potential to influence global gene expression in normal and tumor cells, but also open the door to an alternative strategy of targeting the well-characterized amplification of the EGFR locus in GBM.