Enabling the therapeutic delivery for spinal cord glioma by epidural light-guided modulation of blood-spinal-cord barrier - Abstract Our proposal focuses on addressing the significant clinical challenges associated with intramedullary spinal cord tumors (IMSTs). While IMST represent approximately 2% of all Central Nervous System (CNS) neoplasms, with higher prevalence in the pediatric population, they are associated with high morbidity and pain and are invariably fatal. Surgical options for diffusely invasive IMST (gliomas) are limited to partial debulking for palliation due to the anatomical complexity and high risk of injury. Radiation, a standard of care for supraspinal gliomas must be be used with caution and at lower doses due to the risk of radiation induced myelopathy. To add to the dearth of therapeutic options, delivery of the great majority of chemotherapies and targeted drugs is limited by the blood-spinal cord barrier (BSCB). Focused ultrasound (FUS), which is able to disrupt the BBB and is under investigation for intracranial GBM, has limited utility for IMST due to the inability of FUS to penetrate through the dense vertebral processes without risking thermal injury. There is also ample evidence that drugs delivered through the intrathecal/CSF route, while effective of treating leptomeningeal disease, fails to gain access to the brain/spinal cord parenchyma due to the brain-CSF barrier formed by the glial limitans. To address these challenges, the overarching goal of our proposed work is to develop a novel and minimally invasive method to enhance the spinal cord delivery of otherwise efficacious cancer therapy, test in de novo spinal cord glioma model, and evaluate its application in large animal models (pigs). This is based on our recent work on optically opening the blood-brain barrier using laser pulses and vasculature-targeted gold and iron oxide nanoparticles. We hypothesize that the epidural light-based approach presents a unique advantage to temporarily open the BSCB (epidural OptoBSCB) and enhancing drug delivery to spinal cord tumors. First, light can be delivered minimally invasively into the spinal cord with epidural fiberoptic probes. Second, our preliminary data demonstrate that OptoBSCB can be graded, is entirely reversible, and allows the entry of different therapeutics into the spinal cord. Third, our findings indicate that calcium-mediated mechanobiological mechanisms underpin the blood-brain barrier opening. We plan three aims to advance the therapeutic delivery for IMST. Aim 1 focuses on characterizing the BSCB and OptoBSCB modulation in de novo IMST tumor model with a common BRAFV600E mutation. Aim 2 centers on evaluating the therapeutic activity of Dabrafenib and Trametinib along with radiation therapy and immune checkpoint inhibitor anti-PDL1 antibody, including synergy levels. Aim 3 will evaluate the feasibility of optoBSCB in a large animal model using a custom designed epidural probe to minimally invasively deliver light into the spinal cord. The outcome of our proposed studies will lead to new technology for BSCB modulation and therapeutic delivery, including improved drug delivery and minimally invasive probes for epidural light delivery.
