Targeting ALT-Associated Vulnerabilities in Pediatric High-Grade Glioma

Dr. Jihye Paik, Ph.D. – Weill Medical College of Cornell University, New York, NY

Pediatric high-grade gliomas are among the most aggressive childhood brain cancers, with few effective treatments and poor survival. Many of these tumors carry mutations in a gene called ATRX, which normally helps maintain chromosome ends, or telomeres. When ATRX is lost, the tumor cells switch on an alternative system called ALT (alternative lengthening of telomeres) to keep dividing. While this allows the cancer to grow, it also creates a weakness: these cells experience constant damage at their telomeres and must rely on backup repair pathways to survive. We discovered that ATRX-deficient, ALT-positive gliomas are especially dependent on a protein called FANCM, which helps repair damaged telomeres. When FANCM is blocked, ALT-driven tumor cells die, but healthy cells are largely unaffected. This makes FANCM a highly promising target for therapy. We have already identified small molecules that can mark FANCM for destruction inside tumor cells, a strategy known as targeted protein degradation. In this project, we will refine these FANCM degraders and test them in cell and mouse models of pediatric glioma. Our goal is to determine whether this approach can slow tumor growth and extend survival, without harming normal tissues. By exploiting a unique weakness created by ATRX loss, this research introduces a new treatment strategy for these otherwise “undruggable” pediatric brain tumors, with the potential to improve outcomes for children facing this devastating disease.