MRI-guided focused ultrasound to enhance ME3BP7 delivery as a novel therapy for Glioblastoma

Abstract public domain (NIH RePORTER)

Project Summary I am an Assistant Professor of Neurosurgery at Johns Hopkins, and my clinical practice focuses on brain tumors. I am applying for a mentored surgeon-scientist research career development award to gain advanced training in molecular biology, cancer metabolism, and novel drug delivery strategies to the brain. Glioblastoma (GBM) is a devastating brain cancer with a median survival of just 13 months. Challenges in treatment are largely due to tumor heterogeneity and the impermeability of the blood-brain barrier (BBB). Current treatments offer limited efficacy, necessitating innovative approaches to improve drug delivery and targeting. My project addresses this critical need by leveraging MRI-guided focused ultrasound (MRIgFUS) to transiently disrupt the BBB, enhancing the delivery of ME3BP7, a novel, stable pyruvate analog that targets MCT1, a metabolic transporter overexpressed in over 80% of GBMs. The Specific Aims of the proposal are to: (1) Elucidate the mechanism of action of ME3BP7 in GBM, focusing on its impact on MCT1-dependent metabolism and resistance pathways, and (2) to optimize ME3BP7 delivery across the BBB using MRIgFUS in patient-derived xenograft models. These experiments will validate the potential of MCT1 targeting with ME3BP7 while pioneering a clinically translatable approach for BBB disruption. As a neurosurgeon interested in translational research, I have extensive experience in cancer cell biology, orthotopic murine GBM models, and biomarker-driven drug development, including the successful design and preclinical validation of ME3BP7 in pancreatic cancer models. This K08 proposes building upon my cancer research and drug development postdoctoral training towards a new direction at the interface of metabolic targeting and translational therapeutics. Under the mentorship of Dr. Chetan Bettegowda, an internationally recognized leader in brain tumor research, I will refine my expertise in GBM metabolism, molecular biology, and drug delivery. Specific training goals include: (1) Hands-on training in molecular biology techniques, including CRISPR-Cas9 gene editing and metabolic enzyme quantification; (2) Didactic and experimental training in cancer metabolism, with a focus on metabolic flux analysis; (3) Advanced training in pharmacokinetics and drug delivery, particularly in MRIgFUS for BBB disruption; (4) Formal coursework in biostatistics, grant writing, and research ethics to strengthen scientific rigor and independence. We have created a high-quality educational and mentorship plan to complete this research with a multidisciplinary team of collaborators to help develop my career as an independent clinician-investigator. My scientific advisory committee will also support my overarching career goals and evaluate my progress. This proposal represents a novel research line for which I will be responsible and is specifically designed to help me establish an independent investigation, ultimately advancing the field of GBM therapy by supporting my long-term goal of integrating metabolic targeting with precision drug delivery to the brain.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options due to target heterogeneity and poor drug penetration. Our project combines ME3BP7, a novel molecule targeting the metabolic transporter (MCT1) overexpressed in over 80% of GBM, with MRI-guided focused ultrasound to transiently disrupt the blood-brain barrier and enhance drug delivery. This approach directly addresses the urgent need for new targeted GBM therapies paired with innovative strategies to improve drug delivery to the brain.