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John Y. H. Kim, MD, PhDJohn Y. H. Kim, MD, PhD

Children's Hospital
Boston, Massachusetts
Emily Dorfman Foundation for Children/
American Brain Tumor Association Grantee

Dr. John Kim earned both his MD and PhD from the University of Pennsylvania. Currently, he is a pediatric oncologist on staff at the Dana Farber Cancer Institute and Children's Hospital, and an instructor at the Harvard School of Medicine. Dr. Kim pursued his early interest in biomedical research and coupled it with his interest in the developmental problems of clinical pediatrics. Pediatric neuro-oncology represents the confluence of his interests, and currently, he is well-positioned to pursue his avenues of interest and expertise.

Research Summary
Neurotrophin-3 Treatment and Magnetic Resonance Imaging of Medulloblastoma in an Intracerebral Xenograft Nude Mouse Model

The management of medulloblastoma relies on diagnostic staging, which is currently based on anatomic and radiographic criteria rather than molecular or cellular biological characteristics. In medulloblastomas we have found that the expression of trkC, the neurotrophin-3 (NT-3) receptor, is positively correlated with clinical outcome and programmed cell death (apoptosis). As a potentially therapeutic biological response, NT-3 activated TrkC signaling induces apoptosis in primary medulloblastoma cells both in vitro and in vivo in intracerebral xenografts in nude mice. We hypothesize that NT-3/TrkC-induced apoptosis contributes to patient survival by inhibiting tumor growth in situ, and have established a system for testing whether NT-3 stimulation.ssireases tumor cell death in vivo.

Magnetic Resonance Imaging (MRI) methods provide in vivo visualization of intracerebral medulloblastoma xenografts in nude mice. In addition to normal cranial and brain structures, abnormalities such as neoplasia, hydrocephalus, hemorrhage and edema are readily identified in MRI scans with different techniques. Sensitivity for tumor detection is markedly enhanced by intravenous injection with the contrast agent, gadopentatate dimuglumine (Gd-DTPA). We demonstrate that MRI techniques can accurately visualize normal and pathological features of the mouse brain in vivo,.ssiluding brain tumors, and can evaluate placement of a modified MRI-compatible intra-tumoral NT-3 delivery system.

Using the intracerebral xenograft system, we successfully established the safety of exogenous NT-3 in nude mice. After implantation with human medulloblastoma cells, tumor-bearing mice were treated with NT-3 delivered via intratumoral cannulas from subcutaneous osmotic pumps. Experimental and control mice were followed both clinically and using MRI for tumor progression. Molecular and immunohistochemical techniques were used to directly assess the effects of treatment.ssiluding induction of apoptosis. Parallel studies are ongoing in ptc+/- mice that develop medulloblastomas.

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