DDEL-13. CILIA INHIBITORS SYNERGIZE WITH TEMOZOLOMIDE TO DRAMATICALLY IMPROVE SURVIVAL IN ORTHOTOPIC MURINE MODELS OF GLIOBLASTOMA

Abstract

Abstract Patients with malignant brain tumors such as glioblastoma face a poor prognosis with a median survival of less than two years. Recent glymphatic studies demonstrate the interconnectivity between the fluid in the brain parenchymal and ventricular spaces. We reasoned enhancing the accumulation of a drug in the cerebral spinal fluid (CSF) of the ventricular space will also enhance the accumulation of the drug in the parenchyma where a GBM resides. To improve drug accumulation in the CSF, we modulated the motility of ependymal cell cilia. Ependymal cells coat the ventricles and display motile cilia that mechanically propel CSF through the ventricular space. Impairing ciliary motion could slow down CSF turnover without affecting the overall amount of CSF in the brain and central nervous system. To test these hypotheses, we identified FDA-approved therapeutics that are known to impair airway cilia as a “side effect.” Seven candidate drugs were administered into the ventricle of mice bearing orthotopic GBM in combination with systemic temozolomide. Five of the seven cilia-inhibiting drugs significantly improved overall survival when combined with temozolomide compared to controls. The lead candidate, lidocaine, demonstrated a synergistic relationship with temozolomide, and 100% of animals treated with the combination survived to the study endpoint tumor free. We demonstrate lidocaine can impair cilia motility in vitro and in vivo. Combining intraventricular lidocaine with temozolomide is well tolerated and results in a 2.8-fold increase in brain temozolomide concentration per dose compared to controls. Finally, we validate these data in two human PDX orthotopic xenograft GBM murine models, including an un-methylated MGMT GBM that became sensitive to temozolomide with the combination treatment. These studies offer a new concept for treating malignant brain tumors and potentially a scheme to improve the treatment of additional encephalopathies in the future.