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Abstract

Cancer Research

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease

Published: January 29th, 2021

DOI:

10.3791/62033

1Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, 2Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 3Department of Comparative Medicine, University of South Florida, 4Department of Breast Oncology, H. Lee Moffitt Cancer Center & Research Institute, 5Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, 6Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, 7Department of Medical Oncology, Roswell Park Comprehensive Cancer Center

Abstract

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the "Murine Ommaya." As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.

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Keywords Murine Ommaya

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