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Dr. Donald O'Rourke is interested in the cell and molecular biology of erbB family receptor tyrosine kinases, including the ErbB1/Epidermal Growth Factor Receptor (EGFR) and the p185ErbB2/neu receptor kinases. His laboratory has examined the biochemical features of erbB signal attenuation in normal and transformed cells, with a particular emphasis on glial cells of the central nervous system. Genetic approaches to inhibiting erbB signaling have been employed to characterize domain-specific receptor interactions leading to activated or diminished signaling from erbB receptor complexes, with a particular emphasis on the EGFR kinase. EGFR signaling is deregulated in a large fraction of malignant glial tumors. Additionally, studies of erbB receptor interactions modulating normal neuronal and astrocyte cell growth and survival are presently being addressed via the use of primary explant cell culture systems and transgenic lines.

In addition to studying the mechanisms of cell growth and transformation induced by EGFR family proteins, Dr. O'Rourke has developed receptor-based strategies which facilitate apoptotic cell death in EGFR-containing glioblastoma cells. Both genetic and pharmacologic inhibition of EGFR signaling results in apoptosis following the induction of genomic damage by gamma-irradiation. The biochemical basis for this apoptotic response is being characterized in his laboratory at present. One translational aim of these studies is to enhance the effects of cell death resulting from radiation therapy of malignant astrocytomas through inactivation of the EGFR kinase. Collaborative efforts are ongoing to develop new classes of anti-erbB receptor pharmaceuticals that are based on structural design.

Dr. O'Rourke's present research aims can be summarized as follows:

• To understand the mechanisms of cell death in erbB receptor-containing glial cells during normal development and following oncogenic transformation.
• To understand the biochemical mechanisms of erbB signal attenuation in transformed glial cells of the central nervous system.
• To apply this understanding to the design of rational, biologically-based drugs for diseases such as malignant glioma and CNS neurodegenerative pathologies.

Dr. Sutton's research interests are in the areas of brain tumor treatment and biology, and fetal surgery. Recent work has focused on quality of life issues related to multimodality treatment of pediatricbrain tumors, the use of magnetic resonance spectroscopy in diagnosis,
and, with other members of the neurooncology group at CHOP, basicmechanisms of cellular proliferation in tumors.

Dr. James M. Schuster is interested in the basic mechanisms of prostate cancer metastasis to the spine. Prostate cancer has a very strong predilection for spread to bone with the spine being a major area of metastatic involvement. Spinal cord compression is the first sign of prostate cancer in an estimated 12-19% of patients, and loss of ambulatory function significantly shortens life expectancy. In addition to neurologic compromise, spinal involvement and pathologic fractures are a major source of lifestyle limiting pain and suffering. Current therapies including radiation, surgery, and androgen ablation generally only provide temporary relief. We are interested in the role of growth factors such as IGF-1 in tumor proliferation in bone and are working to develop specific local therapy for metastatic disease.

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