Glioma stem cells, plasticity, and potential therapeutic vulnerabilities

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, arising from glial cells in the central nervous system. The current standard of care for GBM involves surgical resection, followed by temozolomide-based chemotherapy, radiation, and tumor-treating fields. Despite this aggressive standard of care regimen, GBM remains almost universally fatal because of its ability to overcome even the most aggressive therapeutic interventions. Current research on the mechanisms underlying this resistance to therapy has illuminated GBM as a highly plastic tumor. This plasticity is hypothesized to be regulated by changes in epigenetic states which then drive therapeutic adaptation and recurrence by altering gene expression profiles of cells in real time to respond to therapeutic pressures exerted by standard-of-care treatment. Importantly, this plasticity results in heterogeneity, which has been connected to both clonal populations within the tumor and a niche of glioma stem cells (GSC) that can go on to repopulate the tumor bulk post therapy. Unfortunately, targeting this plasticity with bulk inhibitors of epigenetic modifications has been unsuccessful in GBM. This is likely due to a combination of poor penetrance of inhibitors into the brain as well as toxic off-target effects of bulk inhibition in an organ as complex as the brain. In this chapter, we discuss the current research behind epigenetic plasticity in GBM and its role in promoting tumor resistance to therapy. We also delve into the research behind the possibility of more targeted therapies designed to reduce bulk toxicity while going after vital cellular targets such as the GSC niche or specific pathways activated during response to therapy. Ultimately, a deeper understanding of these topics may lead to a better treatment paradigm for this devastating disease.