Neuro-Oncology research at Penn 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.
Donald O'Rourke, MD, as director of the human brain tumor tissue bank at the University of Pennsylvania, has examined the biochemical features of erbB signaling 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 due to mutation in a large fraction of malignant glial tumors, particularly glioblastomas.
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 radiation therapies.
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. Additionally, a recent focus of translational research is to develop ways to use MRI techniques to evaluate expression of mutated EGFR proteins in glioblastomas and response to targeted therapies.
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 of astrocytes.
- 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 gliomas.
- To develop methods of molecular imaging of EGFR proteins using advance MRI technologies.
Leslie M. Sutton, MD, chief of neurosurgery at the Children's Hospital of Philadelphia (CHOP), has research interests 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 pediatric brain tumors, the use of magnetic resonance spectroscopy in diagnosis, and, with other members of the neuro-oncology group at CHOP, basic mechanisms of cellular proliferation in tumors.
James Schuster, MD, PhD, has an interest and expertise in treating tumors of the spinal cord and spinal column. He is especially interested in treatment of metastatic involvement of the spine from other primary tumors including lung, breast, renal, and prostate cancer. He is the institutional primary investigator of an observational clinical trial investigating surgical and radiation treatment of metastatic spinal disease (AOSpine- Surgical Versus Nonoperative Treatment of Metastatic Epidural Spinal CordCompression: Quality of Life and Cost-Effectiveness Outcomes). Dr. Schuster's oncology interests also include primary brain tumors and he is the institutional primary investigator for a vaccine trial for glioblastoma multiforme (Phase II/III Study of CDX-110 in Patients With GBM).