Syngn: a novel patient-specific drug-matching strategy in glioblastoma

Abstract AIMS The alteration of the glioblastoma genome by epigenetic mechanisms that share functions with normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC), is a key piece of evidence that links brain cancer pathogenesis with dysregulated stem cell functions. A patient-specific comparison of glioblastoma cells with NSC, a putative cell of origin of at least a proportion of these tumours, is not feasible as patient-matched endogenous NSC are not surgically accessible and all epigenetic studies in glioblastoma have so far compared epigenetic changes of different tumours with each other or to comparators obtained from foetal brains or an unrelated donor. We reasoned that availability of matched GIC and NSC pairs would allow to identify crucial epigenetic differences on a patient-specific basis and would provide essential therapeutic contrast to define disease-and patient-intrinsic biomarkers of drug response that are less confounded by germline variation. METHOD We have harnessed state-of-the-art stem cell technologies and next-generation sequencing methods to compare the epigenetic and transcriptional profile of IDH-wildtype glioblastoma with that of patient-matched normal expanded potential stem cell-derived NSC (iNSC). RESULTS We demonstrate that integrated analysis of the transcriptome and DNA methylome of GIC/iNSC pairs identifies druggable target genes (PTGER4, ALDH3B1, NTRK2 and others) in a proportion of patients and we validate this patient-specific prediction of drug response at pre-clinical level in 3D synGLICO and in in vivo models. CONCLUSION We provide proof of principle that the SYNGN platform can identify patient-specific druggable targets in glioblastoma.