Abstract 839: The clinical C/EBPβ antagonist peptide lucicebtide synergizes with molecularly targeted therapies in GBM

Abstract Glioblastoma (GBM) is the most common and aggressive malignant brain tumor, with median overall survival (OS) following standard-of-care treatment of 15-18 months and 5-year survival of less than 10%. Despite extensive characterization of the genetic lesions driving GBM, there has been no improvement on the overall natural history of the disease, mostly due to the cellular and genetic heterogeneity of these tumors. CCAAT/Enhancer Binding Protein β (C/EBPβ) is a transcription factor identified as a master regulator of the mesenchymal transition in GBM. Lucicebtide (ST101) is a C/EBPβ antagonist peptide that was evaluated in a Phase 2 clinical study in patients with recurrent and newly diagnosed GBM (NCT04478279) and has shown durable responses in a subset of patients. We have previously demonstrated that lucicebtide anti-tumor activity is due to both direct cancer cell death and immune-activation within the tumor microenvironment. Here we investigated whether lucicebtide may synergize with targeted therapeutic strategies against genetic dependencies or immune checkpoints in GBM. We adopted a synthetic lethal CRISPR screen approach in which gain-of-function drivers that are mutated in more than 5% of GBM patients in publicly available datasets (EGFR, PDGFRA, PI3KCA, MDM2, MDM4, CDK4) were suppressed in the presence or absence of lucicebtide in three genetically characterized GBM lines. Our data identified that EGFR suppression by multiple independent sgRNAs was synthetic lethal in the presence of lucicebtide. We confirmed these findings by performing checkerboard assays of lucicebtide in combination with chemically distinct EGFR inhibitors, indicating that lucicebtide synergizes with EGFR inhibition (EGFRi) in GBM. We further characterized the mechanism of action of EGFRi-lucicebtide combination on known signal transducers of EGFR in the presence or absence of ST101. Finally, we explored the relationship between transcriptional signatures of C/EBPβ activity and EGFR mutational profile in publicly available GBM datasets, identifying potential genetic biomarkers for prediction of maximal efficacy of this combination. These studies demonstrate the potential of lucicebtide to enhance the activity of molecularly targeted therapeutics such as EGFRi that are typically not effective when used as monotherapies in GBM. Biomarker analysis utilizing GBM genetics and signatures of C/EBPβ activity was performed to identify potential target populations likely to benefit from ST101 combinations. Citation Format: Julia Diehl, Ricardo Ramirez, Mark Koester, Franco Abbate, Lila Ghamsari, Abi Vainstein-Haras, Barry J. Kappel, Claudio Scuoppo, Jim A. Rotolo. The clinical C/EBPβ antagonist peptide lucicebtide synergizes with molecularly targeted therapies in GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 839.