Medulloblastomas (MBs) are the most common malignant brain cancers in children and frequently disseminate to the leptomeninges. Leptomeningeal MB carries poor prognosis and thus constitutes an unmet clinical need. Its therapy is suboptimal since drugs frequently do not effectively enter the cerebrospinal fluid (CSF) or are washed out rapidly. Thus, the leptomeninges are a sanctuary from systemic therapy. It is therefore imperative to develop novel approaches for drug delivery into the CSF to treat leptomeningeal MB. Our goal is to develop a new clinical approach to effectively treat leptomeningeal MB. We propose metronomic (multiple small frequent infusions) drug administration directly into the brain ventricles to achieve maxi- mal therapeutic efficacy. Therapy will be via a novel, wirelessly-operated, programmable, implantable, re- fillable micropump developed by Dr. Meng, which is now ready for preclinical testing in this R21. The main innovations of this pump are the combination of wireless control, programmability, and miniaturized packaging. Our pilot data show that this refillable pump can reliably deliver hourly infusions into the CSF over prolonged periods. In a small pilot experiment, topotecan given metronomically into the CSF via this pump induced complete remission in a mouse with leptomeningeal MB, whereas similar dose delivered intraperitoneally had no benefit. Thus, metronomic delivery of chemotherapy into the CSF may prove more effective and less toxic than systemic delivery. This R21 will test our pump in treatment of leptomeningeal MB in mice. Treatments such as chemotherapy, anti-GD2-mediated immunotherapy and others may benefit from metronomic intra-ventricular delivery via our novel wireless programmable implantable refillable pump. We hypothesize that metronomic therapy delivered directly into the CSF by our pump will be more effective against leptomeningeal MB in mice compared to the same agents delivered via other schedules/routes. We will test this using our pump in two Specific Aims: 1) To test pre-clinical safety and efficacy of metronomic intra-ventricular chemotherapy via our micro-pump in mice carrying leptomeningeal MB compared to drug delivery via other routes and schedules; 2) To test safety and efficacy of intra-ventricular anti-GD2-based immunotherapy via our micro-pump in mice carrying leptomeningeal MB compared to anti-GD2 delivery by other routes and schedules. Results from this R21 will establish principles for dosing regimen(s) for phase I clinical trials using a scaled-up version of this pump and provide the pre-clinical data fo this novel clinical approach. This work is of high significance as our novel pump will allow effective drug delivery into the leptomeninges. The clinical impact of this approach is wide, since it may also apply to other diseases or other cancers affecting the brain and spinal cord for which sustained delivery of drugs is a challenge. Thus, our application is highly novel and has high significance and potential for strong impact in an area where there is a great unmet need.
Medulloblastoma is the most common malignant brain cancer in children, with frequent spread to the linings of the brain and spinal cord (i.e., leptomeningeal metastasis), where treatment cannot enter effectively, making this an important health problem. Our proposal will test a new mode of metronomic chemotherapy and immunotherapy delivered directly to leptomeningeal metastases of medulloblastoma in mice, using a novel implantable wireless programmable refillable micropump developed by us. Successful testing will serve as preclinical data to translate use of a scaled-up pump for a first-in-humans clinical trial and may also allow subsequent expansion to other brain-centered diseases that can benefit from leptomeningeal drug delivery and thus further increase the impact of this work.
