HBEGF as a novel therapeutic target for Diffuse Midline Glioma

Dr. Oren Becher, M.D. – Icahn School of Medicine at Mount Sinai, New York, NY

Diffuse Midline Glioma or DMG is a type of brain cancer that arises in children and is still mostly incurable. While we have made progress by identifying the genetic drivers that give rise to DMG, this knowledge has so far failed to prolong the lives of most children with DMG. The Becher lab has been developing models for DMG since 2010 and thus far our modeling has required the use of a particular growth factor called PDGFA/B to activate a cell surface receptor called PDGFRA which signals internally within the cell to promote cell division, and tumor growth. Recently we have discovered that another growth factor, HBEGF, -which activates a different cell surface receptor called EGFR- can substitute for PDGF and may be an important ligand, or receptor, to model DMGs with H3.1K27M and EZHIP as co-drivers. We believe this is an important advance in the field and we will share this new model with the research community. Here we propose to characterize this new model of DMG that is driven by HBEGF and EZHIP, to study which genes EZHIP regulates in the context of HBEGF, as well as identify mechanisms of resistance to EGFR inhibition in a mouse model of DMG driven by HBEGF. In summary, this work will provide an important new research tool for the DMG community and may provide new insight as to why several inhibitors of EGFR have failed in the clinic to prolong the lives of children with DMG.