Epigenetic pathways and plasticity in brain tumors.

Clinical studies have shown that treating many primary brain tumors is challenging due in part to the lack of safe and effective compounds that cross the blood brain barrier (BBB) (Tan et al., 2018). However, if we were to imagine that we have ideal BBB penetrant compounds that target brain tumor cells selectively, recent studies suggest that those compounds may still not be effective due to the heterogenous nature of the tumors. In other words, there are many subsets of cells within a brain tumor and we need compounds to target all those different populations. This is a considerable challenge. Targeting of the cells of origin of these brain tumors is equally important. And yet another impediment we face is that brain tumor cells-of-origin may be protean and are able to differentiate into other cell types to drive recurrence. Therefore, an ideal BBB-penetrant compound targeting a cell-of-origin in a brain tumor may be ineffective due to the cell's ability to differentiate into another resistant cell type. One possible means of combating the plastic nature of these cells is targeting epigenetic pathways used by the cells to differentiate into other cell types along with standard treatment regimens. We summarize here some of the epigenetic pathways that have been shown to be active in three different primary brain tumors, glioblastoma (GBM), medulloblastoma (MB), and diffuse intrinsic pontine glioma (DIPG). We also compare single-cell sequencing RNA analysis of these tumors in order to identify common epigenetic pathways to treat in the respective cells-of-origin for these tumors. Lastly, we discuss possible combination therapies that may be generalizable for treating these and other brain tumors using mutli-omics approaches. While our focus on these three tumor types is not exhaustive and certainly other brain tumors can have similar mechanisms, there has been significant recent evidence linking epigenetics, plasticity and intratumor heterogeneity in these tumors.