Predicting Sensitivity to a Novel Olig2 Inhibitor in Glioblastoma

Longwei Zhang

Mentor: Dr. Nagi Ayad, Department of Oncology, Georgetown University Medical Center

Date/Time: August 22nd, 2023 at 1pm.

Abstract: Glioblastoma (GBM) is the most common adult malignant primary brain tumor. OLIG2 is a transcription factor that is a potential target in GBM. It normally is expressed within progenitor cells during brain and spinal cord development but is reactivated in high grade gliomas (HGG) including GBM. OLIG2 expression propels the proliferation, invasiveness, and radiation resistance of HGG cells and tumors in animal models. Recently, a novel Olig2 inhibitor (CT-179) has been described, which inhibits the transcriptional regulatory activity of Olig2. However, the selective efficacy for distinct GBM transcriptional cell states and subtypes of CT-179 have not yet been described.  It is essential to determine this as GBM is known to be a heterogenous tumor, and drug combinations are needed for yielding a robust treatment response.

In order to identify CT-179 sensitive and resistant cells, tumor cells were categorized according to their distinct transcriptional states. By analyzing the differential gene expression patterns resulting from Olig2 treatment, we developed a CT-179 response signature. This signature was subsequently utilized to analyze GBM single-cell RNA-seq data, yielding predictions regarding drug responses. Furthermore, we examined bulk RNAseq data from both TCGA and of cells from the Mayo Clinic’s Brain Tumor Patient-Derived Xenograft National Resource (PDX cells), substantiating varied responses of distinct cell subtypes to the drug. Importantly, we validated our predictions through wet-lab assessment of drug sensitivity in these same PDX cell lines. For future research, we will generate CT-179 combination therapies based on our cell state selectivity predictions and test these in vitro and in vivo models of GBM.