Mentor Name: Paul Knoepfler

Pediatric high-grade diffuse midline gliomas (DMG) with histone H3.3 mutations are rapidly fatal tumors and key gaps exist in the field’s understanding of targetable DMG dependencies. Innovative insights into DMG mechanisms are urgently needed as the basis for new therapies. Our overall goal in this proposal is to address these troubling gaps and ultimately develop effective DMG therapies. Our new data indicate that microRNAs (miRNAs) represent a novel, likely targetable element of DMG programming. miRNAs regulate a range of cellular processes and are implicated in many human diseases, including cancer. More specifically, the let-7 family of miRNAs act as potent tumor suppressors in many cancers by repressing oncogenes like MYC and RAS factors. The expression of let-7 miRNAs is suppressed by the increased LIN28A/B evident in many tumors. In this way, LIN28A/B and let-7 miRNAs together represent a central oncogenic axis, which has been studied in many tumors. However, the LIN28-let-7 axis is not well-understood in H3.3 mutant DMG. Our specific objective in the proposed summer research project is to define the functions of the LIN28-let-7 axis in DMG as a novel therapeutic target in DMG. The focus will be on testing specific LIN28 inhibitors in DMG and also knocking down LIN28 expression. We predict that LIN28 inhibition will lead to reduced DMG proliferation and increased cell death.