Research And Grants

Leveraging Epigenetic Alterations for Therapy of Diffuse Midline Glioma

Diffuse midline glioma (DMG) is a uniformly fatal brainstem tumor of childhood with no effective therapies. Given the failure of chemotherapy and radiation against DMG, we are pursuing strategies to enable effective immunotherapy for this disease. A major roadblock to immunotherapy is that DMG cells effectively ‘hide’ from the body’s immune system. We now understand that DMG cells rely on “epigenetic” modifications, or chemical marks that regulate whether genes are turned on or off. This presents a selective vulnerability in DMG cells that makes them sensitive to epigenetic drugs. We have shown that use of existing, FDA-approved drugs to target epigenetic regulators can activate immune signaling in DMG cells and cause expression of new targets that can be recognized by the immune system, creating an avenue for converting this immunologically ‘cold’ tumor into a ‘hot’ one that can be effectively targeted. In order to validate this strategy for translation to patients, it is necessary to use a mouse model with an intact immune system, unlike the immunodeficient mouse models that are typically used to model human brain tumors.  We will employ a powerful DMG mouse model in collaboration with Dr. Oren Becher in order to test the effect of epigenetic therapy on immune signaling in DMG, with the goal of rapid translation of these therapies to patients who urgently need better treatments.