Kindred – Elucidating the mechanisms of dissemination and therapy resistance in pediatric low-grade glioma
Award: $650,000 over 3 years (awarded 2026)
Principal Investigator: Adrian Levine, MD, PhD, The Hospital for Sick Children (SickKids), Toronto
Funding Partners: Team Syren, Kindred Foundation, Cancer Research Society
Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children. While many grow slowly and can be managed successfully, a small but devastating subset spreads throughout the brain and spinal cord via the cerebrospinal fluid (CSF). These cases known as disseminated pLGG are associated with significantly worse outcomes, limited treatment options, and high lifelong morbidity. Yet, despite their severity, the biological mechanisms that drive dissemination and treatment resistance remain poorly understood.
This project seeks to address that gap by uncovering why certain pLGG tumors spread and why they eventually stop responding to targeted therapies, even when those therapies initially show promise. Building on leadership of the world’s largest international disseminated pLGG consortium, encompassing more than 250 patients the research team has already demonstrated that dissemination is rarely driven by a single genetic mutation. Instead, early findings point to non-genetic factors and the tumor microenvironment, particularly changes in the CSF and immune signaling, as key drivers of aggressive behavior.
To translate these insights into meaningful clinical impact, this project integrates four complementary approaches. First, researchers will analyze CSF samples using advanced proteomics, metabolomics, and single-cell sequencing to identify molecular changes that create a permissive environment for tumor spread. Second, they will study tumor samples collected before and after targeted MAPK-pathway therapies to uncover mechanisms of treatment resistance. Third, patient-derived cell lines and organoids will be used to test new combination therapies designed to overcome resistance. Finally, the development of the first in vivo mouse model of pLGG leptomeningeal dissemination, enabling direct testing of novel therapies and drug-delivery strategies.
Together, these efforts create a powerful, end-to-end translational framework linking patient samples, advanced molecular profiling, functional models, and preclinical testing to accelerate the development of smarter, more durable treatments for children with the most aggressive forms of pLGG.
