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Development of a Comprehensive Direct Drug Delivery Platform for the Treatment of Diffuse Midline Glioma
Diffuse midline glioma (DMG) is a devastating pediatric brain cancer with approximately 300 children diagnosed per year and a dismal 5-year survival rate.The deep, central location, infiltrative growth pattern, and preservation of the blood-brain barrier (BBB) in this tumor have relegated traditional therapeutic approaches, including surgical resection and systemic chemotherapy, ineffectual. . Importantly, high systemic doses of chemotherapies are required to achieve efficacious levels in the central nervous system (CNS) in children with DMG, which secondarily generate very strong drug toxicities. Our overarching objective is to design novel and effective therapeutic protocols for DMG patients. To accomplish this, our game-changing strategy will consist of using a comprehensive set of drug delivery and drug imaging methods, including convection-enhanced delivery (CED), focused ultrasound BBB disruption (FUS-BBBD), intra-arterial delivery (IA), and intrathecal delivery (IT) that will more effectively target DMG tumor sites, while avoiding the toxicities associated with conventional administration of drug therapies. As proof of concept, we have identified several drugs that act in synergy with CDK4/6 inhibitors to inhibit DMG cell growth through our collaboration with Dr. Thomas (NIH-NCI). We will compare the safety and efficacy of these therapies when used in genetic and xenograft mouse models of DMG via conventional systemic delivery (i.e. intravenous) and various methods at the forefront of enhanced drug delivery (CED, FUS-BBBD, IA, IT). We will then expand this effort to additional drug combinations that will include epigenetic modulators. Finally, to refine our drug delivery methods and ensure that our therapies adequately reach tumor sites, we will radiolabel our compounds, which will allow us to track their volume of distribution in real time with molecular imaging techniques. Overall, this is an ambitious and game-changing project incorporating a state-of-the-art preclinical platform for enhancing our understanding of enhanced drug delivery techniques and real-time intraoperative monitoring of drugs in the brain. We expect the establishment of this platform to act as an incubator for the translation of many cutting-edge therapies to early-stage clinical trials in the fight against DMG.