Rebound and Resistance of Pediatric Low-Grade Gliomas to MAPK Pathway Inhibitors (Expanded Funding)

Award: $300,000 over 2 years (awarded 2024)
Principal Investigators: Pratiti (Mimi) Bandopadhayay, MBBS PhD, and Rameen Beroukhim, MD PhD, Dana-Farber Cancer Institute
Funding Partners: Jacks Drive 55 Foundation through PBTF’s PLGA Fund

This grant builds on the successful results of the Dana-Farber Cancer Institute research team’s work on optimizing targeted inhibition to overcome resistance and/or rebound growth in the treatment of pediatric low-grade gliomas (pLGGs) and their study of the biological factors and cellular changes that contribute to some pLGGs’ resistance to treatment and subsequent regrowth.

Through the Pediatric Brain Tumor Foundation’s previous funding, Dr. Pratiti (Mimi) Bandopadhayay, Dr. Rameen Beroukhim, and their team successfully generated three isogenic mouse and human model systems to evaluate the cellular changes associated with induction of BRAF and FGFR family oncogenes in pLGGs. Their research confirmed that the mouse neural stem cell models that constitutively express pLGG-relevant oncogenes are sensitive to MAPK pathway inhibition.

Building on this research, the team now is optimizing the induction conditions for the model systems, expanding their experiments to additional isogenic models, and evaluating MEK inhibition’s effects on apoptosis and cell-cycle arrest. The additional funding will also enable researchers to apply single-cell RNA-sequencing and CRISPR-cas9 apoptosis screens to evaluate changes in cell state with treatment and on withdrawal, and to identify genes that induce apoptosis in the presence of MAPK inhibitors.

In addition to the Pediatric Brain Tumor Foundation’s expanded funding, the results generated by our early seed funding have led Dana-Farber Cancer Institute’s research team to secure a grant from the Department of Defense, opening the door to investigating other important aspects of rebound and resistance.