HG-112: LOCAL DELIVERY OF RADIOSENSITIZING NANOPARTICLES FOR THE TREATMENT OF PEDIATRIC BRAINSTEM GLIOMAS

Diffuse intrinsic pontine gliomas (DIPGs) are clinically aggressive, unresectable tumors in children. Despite numerous clinical trials, there has been no significant improvement in survival for DIPG over the past 30 years. Systemic therapies are often given concurrently with radiation therapy (RT) or chemotherapy to enhance local control; however current systemic chemo- and radio-sensitization strategies are limited by poor drug penetrance through the blood brain barrier and rapid drug clearance. To address these limitations, we developed polymeric nanoparticles (NPs) encapsulating radiosensitizers that are locally delivered to intracranial tumors via convection-enhanced delivery (CED), and which provide controlled release of drug over time. We established a proof-of-concept with VE-822, a small molecule inhibitor of a key DNA damage response protein, Ataxia Telangiectasia and Rad3-related (ATR). In vitro testing of pediatric glioma cells and patient-derived DIPG spheroids demonstrates that drug-NPs combined with RT confer increased inhibition of DNA repair over free drug and increased radiosensitization in clonogenic survival assays. In vivo CED of NPs demonstrate sufficient distribution and intracellular uptake of NPs throughout the region of delivery, and persistent intracranial drug levels for up to 10 days following CED compared to less than 5 days following CED of free drug. In vivo efficacy studies demonstrate that CED followed by a fractionated RT course is well tolerated by xenograft-bearing rats, with final survival endpoints still pending. Overall, CED of radiosensitizing NPs appears feasible, effective, and represents a promising therapeutic strategy for aggressive gliomas such as DIPG.