MODL-36. EX VIVO GSC CULTURES RETAIN PATIENT-UNIQUE HALLMARK GENE EXPRESSIONS AND PREDICT PATIENT RESPONSE TO TMZ MORE SPECIFICALLY THAN MGMT PROMOTER STATUS

Abstract

Abstract BACKGROUND Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). METHODS DNA and RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Drug response readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. RESULTS Tumor DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. Patient-specific hallmark gene expression levels were retained in vitro. Functional screening for TMZ sensitivity yielded three response categories (responders, intermediates and non-responders) which significantly correlated with patient survival, therewith providing a more specific response prediction than the binary MGMT marker. Transcriptome analysis of GSCs and parental tissues identified 121 genes related to TMZ sensitivity and overall survival, of which 21, including MGMT, could be validated in external datasets. CONCLUSION GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma patients.