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Clinicians and scientists at the University of Pennsylvania are involved in a large variety of research endeavors aimed at understanding the basic biology of glial tumors. The National Institute of Health (NIH)/National Cancer Institute (NCI), the American Cancer Society, the Department of Veterans Affairs and the Brain Tumor Society are among several agencies that have funded this research. Examples of some of our current research efforts is given below.

Signal Transduction:
Dr. Donald O’Rourke (Department of Neurosurgery) is studying the molecular biology of the erbB family receptor tyrosine kinases, including erbB1/EGFR and p185ErbB2/neu. Studies are aimed at elucidating the mechanisms of erbB signal attenuation in normal and transformed astrocytes. Using several approaches to inhibit erbB signaling this group has characterized domain-specific receptor interactions that lead to activated or diminished signaling from erbB receptor complexes. In addition to studying the mechanisms of cell growth and transformation induced by EGFR family proteins, Dr. O'Rourke has developed receptor-based strategies that facilitate apoptotic cell death in EGFR-containing glioblastoma cells. Following the induction of genomic damage by gamma-irradiation, studies have shown that genetic or pharmacologic inhibition of EGFR signaling results in apoptosis. The biochemical basis for this apoptotic response is being characterized. One translational aim of these studies is to enhance the effects of cell death resulting from radiation therapy of malignant astrocytomas through inactivation of EGFR kinase. Collaborative efforts are ongoing to develop new classes of anti-erbB receptor pharmaceuticals that are based on structural design.

Dr. Amit Maity (Department of Radiation Oncology) is studying vascular endothelial growth factor (VEGF) signaling in glial tumors. VEGF is a key mediator of angiogenesis and is over-expressed in many cancers, including primary malignant glial tumors. In many in vivo models, inhibition of VEGF function arrests tumor growth. While hypoxia has long been recognized to be a potent inducer of VEGF, VEGF can also be expressed in a normal oxygen environment (normoxia). Evidence indicates that angiogenesis may develop in tumors before they have grown to a size large enough to contain hypoxic regions, suggesting that angiogenic factors may be expressed by these tumors under normoxic conditions. In contrast to the induction of VEGF mRNA under hypoxia that involves the hypoxia-inducible factor-1 (HIF-1), the upregulation of VEGF under normoxic conditions is not well understood. Dr. Maity is investigating the mechanisms of VEGF up-regulation in normoxia by alterations commonly found in glial tumors such as EGFR activation and mutations in Ras and PTEN.

Gene Transfer:
Malignant glial tumors have received substantial attention as targets for gene therapy. Gliomas are highly infiltrative into surrounding brain, preventing complete resection. However they rarely metastasize outside the brain and their growth is therefore, relatively well localized, simplifying the targeting of gene vectors to the tumor. While the systemic delivery of viral (and other) vectors to widespread systemic metastases is currently not achievable with high efficiency and low toxicity, local vector delivery to the bulk of a brain tumor can be achieved through either stereotactic injection or infiltration of residual tumor with vector at the time of resection. The direct injection of vectors limits systemic exposure to the therapeutic agent and therefore, minimizes systemic toxicity.

Gene Imaging:
Investigators at Penn synthesized a fluorinated analog of ganciclovir (18F-GCV) suitable for PET imaging. 18F-GCV can be used for non-invasive and quantitative assessment of the extent of gene transfer in vivo. For example, an adenoviral vector expressing HSV-tk and control vector with no transgene were injected intravenously into mice. When 18F-GCV was administered two days later only the bladder was seen on imaging (non-metabolized drug) in control treated animals, whereas the liver was readily imaged in HSV-tk treated animals as expected since it is established that systemically delivered adenovirus preferentially infects liver. Based in these promising results, gene-imaging with serial 18F-GCV PET will be incorporated into the adenoviral HSV-tk trial noted above. Investigators at Penn are also synthesizing alternative chemical substrates for HSV-tk that may prove superior for imaging (i.e. penciclovir, an analog of GCV that has greater intracellular stability).

Tumor Hypoxia:
Dr. Sydney Evans (Department of Radiation Oncology) is developing methods to measure glial tumor hypoxia in an effort to determine relationships to prognosis and response to therapy. Hypoxia is an important factor in the resistance of brain tumors to radiation therapy. One of the major limitations to attacking this problem has been the inability to identify and quantify the presence of hypoxic cells in individual patients. Recent molecular studies have confirmed that hypoxia-associated factors such as VEGF and HIF-1 are present in brain neoplasms and that PTEN mutations, which are common in GBM facilitate the expression of these genes. Studies on the use of hyperbaric oxygen and tirapazamine have suggested that treatment for hypoxia can modify the outcome of patients with malignant gliomas. Dr. Evans has shown that tumor hypoxia can be measured using the binding properties of 2-nitroimidazole drugs such as EF5. Given intravenously, EF5 binds to hypoxic cells in an oxygen-dependent manner and can be detected in tissues using monoclonal antibody techniques. Furthermore, the formulation of EF5 under study is appropriate for non-invasive imaging.


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