BIOM-29. UNMASKING COPPER DEPENDENCE IN GLIOMA: 19-GENE SIGNATURE FOR PATIENT STRATIFICATION AND TARGETED THERAPY

Abstract Adult-type diffuse gliomas exhibit poor prognosis with limited treatment options. Although copper-targeted therapies have been previously explored in these tumors, they have yet to show significant benefits. To understand the role of copper in glioma biology we performed an in silico data analysis on the TCGA glioma cohorts to identify copper-homeostasis related genes (CHRG) with prognostic significance. This was done to enable patient stratification into appropriate treatment arms for future clinical trials involving copper targeted therapies. Furthermore, in vitro experimentation was performed to validate the functional outcomes observed from the in silico results. 19 CHRGs were identified to have prognostic association from the TCGA glioma cohorts. This gene signature regulates a broad range of cellular processes, including metal homeostasis, metabolism, extracellular matrix organization, and immune cell function. The CHRG signature enabled the development of a predictive model that allowed stratification of patients between high and low risk groups. In vitro spheroid growth assays in both U87 cell lines with or without IDH mutation elicited sustained growth inhibition after 6 days post treatment. Furthermore, copper chelation therapy modified the energy potential of these glioma cells in vitro leading to growth inhibition. This study established a predictive model using 19 CHRGs that enable patient stratification between high and low risk glioma patients. Furthermore, our in vitro experiments show the suitability of targeting intracellular copper to inhibit tumor growth. Further research is needed to understand the underlying mechanisms and explore optimal treatment combinations for improved outcomes. We aim to extend this approach to pediatric gliomas for improved risk assessment and personalized medicine.