Macromolecular therapeutics for neoplastic meningitis

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DESCRIPTION (provided by applicant): The goal of the proposed study is to develop novel, safe, and efficient therapy for neoplastic meningitis (leptomeningeal metastasis of cancer). Neoplastic meningitis is a devastating complication of breast cancer and other solid tumors. Published data suggest that 5-8% of patients suffer from this complication. The median survival is about 3 months, and only 2-4 weeks if not aggressively treated. The current treatment is largely palliative. The leptomeningeal space is well isolated from the rest of the body by the blood-brain barrier (BBB) on one side, and by the blood-cerebrospinal fluid (CSF) barrier on the other, which makes systemic chemotherapy ineffective. Attempts have been made to treat neoplastic meningitis with drugs administered intrathecally. However, the currently available chemotherapeutics are rapidly cleared from CSF. Our studies on the behavior of large molecules in CSF clearly show that they are not rapidly cleared from CSF. Being administered intrathecally, large molecules stay in CSF for several hours or days. This suggests that neoplastic meningitis can be effectively treated by intrathecal administration of soluble large-molecule therapeutics that would distribute in CSF and release an insoluble antineoplastic drug that would (I) stay in the meninges and (II) readily access the meningeal population of cancer cells. The objective of this study is to determine the size of the drug molecule that would enable optimal drug retention in CSF, synthesize a model conjugate of that size, and evaluate in animal models drug distribution in the meningeal compartment, efficacy against meningeal cancer spread, and safety of the model conjugate. The study will utilize a novel macromolecular material and a novel drug release system that have been developed in our laboratory. Both technologies have been successfully used in novel systemic drugs, one of which is presently in Phase I clinical studies. We will synthesize and characterize highly fractionated macromolecules labeled with iodine-124, investigate by PET their retention in CSF, then synthesize a camptothecin conjugate of the optimal size with respect to CSF retention, investigate by PET how the conjugate distributes camptothecin in the leptomeningeal space, determine the maximum tolerated dose of the conjugate, and determine the efficacy of the conjugate in an established animal model of neoplastic meningitis induced by human breast cancer cells. We expect that the study will result in (1) a new approach to developing novel intrathecal therapies for neoplastic meningitis caused by breast cancer, and (2) a candidate chemotherapeutic suitable for further development. PUBLIC HEALTH RELEVANCE: The goal of the proposed study is to develop novel, safe, and efficient therapy for neoplastic meningitis, a devastating complication of cancer caused by the spread of cancer cells into layers of tissues surrounding the brain. Published data suggest that 5-8% of breast cancer patients suffer from this complication, and that the risk of neoplastic meningitis significantly increases on the second relapse of the disease. Presently, there is no effective treatment for neoplastic meningitis, and the median survival of cancer patients who develop this complication is reported to be about 3 months.