Diffuse Midline Gliomas: Challenges and New Strategies in a Changing Clinical Landscape

Simple Summary Diffuse midline gliomas are rare tumors of childhood characterized by a midline location, a diffuse-infiltrative growth pattern, and newly described genetic and epigenetic mutations. Since their first description at the beginning of the 20th century, they have been inoperable and carried a poor prognosis, with median survival shorter than two years. In the last decade, however, new hope is on the horizon thanks to new understanding of these tumors' biology and the development of novel, targeted therapeutics.Abstract Diffuse intrinsic pontine glioma (DIPG) was first described by Harvey Cushing, the father of modern neurosurgery, a century ago. Since then, the classification of this tumor changed significantly, as it is now part of the broader family of diffuse midline gliomas (DMGs), a heterogeneous group of tumors of midline structures encompassing the entire rostro-caudal space, from the thalamus to the spinal cord. DMGs are characterized by various epigenetic events that lead to chromatin remodeling similarities, as two decades of studies made possible by increased tissue availability showed. This new understanding of tumor (epi)biology is now driving novel clinical trials that rely on targeted agents, with finally real hopes for a change in an otherwise unforgiving prognosis. This biological discovery is being paralleled with equally exciting work in therapeutic drug delivery. Invasive and noninvasive platforms have been central to early phase clinical trials with a promising safety track record and anecdotal benefits in outcome.