Targeting Notch in Embryonal Tumors
Background
NOTCH is a key developmental gene that is also involved in many cancers. We and other groups have identified NOTCH activation in pediatric brain tumors, specifically medulloblastoma, DIPG, and atypical teratoid/rhabdoid tumor (AT/RT). Our laboratory has significant experience targeting NOTCH using gamma secretase inhibitors (GSI). This class of drug has good brain penetration and several GSI have been found to be safe and tolerable in pediatric phase I trials. Phase I studies in adults showed efficacy in T-ALL with mild diarrhea as the major side effect, with once-weekly dosing.
Project Goals
In our study, we will determine the efficacy of BMS-906024 in vitro and in vivo in our MYC-driven medulloblastoma cell lines. We will measure proliferation by BrdU incorporation and apoptosis by cleaved caspase and cleaved PARP expression. We will perform orthotopic xenografting and treat mice daily with 5 mg/kg BMS-906024 and measure overall survival. We will have 10 mice in each group to allow us to detect a difference of 20% between groups. Together these experiments will provide the preclinical justification for advancing BMS-906024 into clinical trials for pediatric brain tumors.
