Roadmap toward subtype-specific vulnerabilities in adult glioma

Abstract

AbstractGliomas are the most common primary malignancies in the adult central nervous system (CNS), and over the course of the last decades a wealth of data on their genomic characterization has been acquired. Nevertheless, attempts to stratify patients on the basis of this work has so far conspicuously failed to identify useful treatment targets, and no phase III clinical trials conducted to date have reached a favorable outcome. We suggest that these translational failures are due to inadequacies in classification schemes, which fail to capture the range of biologically distinct entities that give rise to gliomas. Treating gliomas of different subtypes together, rather than as a set of biologically distinct but related tumors, has resulted in a classification scheme rich in unexplained heterogeneities, and has restricted target identification efforts to cell cycle and cell growth regulators. We suggest that this failure of detailed genomic characterizations to identify useful treatment targets requires a re-assessment of our assumptions concerning glioma origins. We propose a re-interpretation of glioma subtypes in the light of knowledge of the developmental pathways of the various neural lineages that make up the adult CNS. Such a developmental subtype-specific classification scheme based on dys-regulated cell fate decisions may not only improve classification and diagnosis but, more importantly, identify potentially druggable subtype-specific developmental vulnerabilities.