Targeting EGFR Co-Amplified Long-Noncoding RNA for Glioblastoma Treatment

NU 2025-335

INVENTORS

• Shi-Yuan Cheng*
• Xiaozhou Yu
• Bo Hu
• Runxin Wu
• Xiao Song

SHORT DESCRIPTION

This invention provides compositions and methods for inhibiting ELDR and HELDR, two long non-coding RNAs (lncRNAs) that are frequently co-amplified in glioblastoma (GBM) with the epidermal growth factor receptor (EGFR) gene, and which drive tumorigenesis independently of EGFR signaling.

BACKGROUND

GBM is the most malignant primary brain tumor in adults. Amplification and/or mutation of EGFR occurs in more than half of patients; however, therapeutic targeting of EGFR has show limited clinical benefit, regardless of EGFR amplification or mutation status. Although several canonical mechanisms – including signaling redundancy among receptor tyrosine kinases, feedback regulation, and pathway crosstalk – have been implicated in resistance to EGFR-targeted therapies, they do not fully account for the persistent therapeutic failure, suggesting the involvement of additional, non-canonical regulatory layers. Thus, there is a need for novel therapeutic targets that improve the efficacy of anti-EGFR therapies.

ABSTRACT

The inventors discovered a novel lncRNA, HELDR, that promotes malignancy by binding to genomic DNA at promoters, recruiting the co-activator p300, and activating KAT7 transcription, leading to histone acetylation and expression of genes critical for tumor progression and resistance to EGFR inhibitors. Simultaneously, they found that the ELDR lncRNA enhances the oncogenic activity of BMI1, a component of Polycomb Repressive Complex 1, by disrupting its interaction with the tumor suppressor protein PURA. Targeting ELDR or HELDR using agents like antisense oligonucleotides, guide RNAs, or shRNAs, or inhibiting their downstream effectors BMI1 or KAT7 with small molecules, resulted in marked anti-tumor efficacy. This approach, especially when combined with EGFR inhibitors, significantly reduces tumor volume and enhances survival in EGFR-amplified glioblastoma models.

APPLICATIONS

• Therapeutic Drug Development – This invention provides specific agents (ASOs, gRNAs, shRNAs, small molecules) for inhibiting novel targets (ELDR, HELDR, BMI1, KAT7).
• Combination Therapies – Novel compositions can be used in combination with anti-EGFR therapies to treat EGFR-amplified cancers.

ADVANTAGES

• Enhanced efficacy in EGFR-amplified GBM – Inhibiting ELDR, HELDR, or their downstream effectors results in significant antitumor effects in PDX mouse models, which are further enhanced when combined with anti-EGFR therapies.
• Overcoming resistance through novel mechanisms – Addresses a previously unrecognized mechanism of resistance to current EGFR inhibitors.
• Addressing intratumoral heterogeneity – Offers a strategy to mitigate GBM genetic diversity, potentially leading to more uniform treatment responses.

PUBLICATION

Yu et al. An EGFR Co-Amplified and De Nono Long Noncoding RNA HELDR Promotes Glioblastoma Malignancy through KAT7-Driven Gene Programs. Nature Cell Biology, 2026.

IP STATUS

A US provisional patent has been filed.

ASO-targeting HELDR synergistically enhances anti-GBM activity of EGFR inhibitor Erlotinib. e, The workflow of the animal experiment. f, BLI images. g, Kaplan-Meier analysis for mice bearing GBM6 brain tumor xenografts with indicated treatments.