The Research Foundation of The American Association of Neurological Surgeons continues its excellent track record of supporting worthy neuroscience research. As of June 1999, four clinicians funded by the Research Foundation were completing their projects. It is anticipated that their names will become familiar to you as their research unfolds. Following are summaries of their work thus far.
1997 Research Fellow: Lilyana Angelov, MD, MSc, University of Toronto
Chair:Charles Tator, MD, PhD
Sponsor:Abhijit Guha, MD
Project Title: Vascular Endothelial Growth Factor (VEGF) Expression and Receptor Inhibition in Human Peripheral Nerve Tumors.Project Update: We postulated that VEGF and its cognate receptor, VEGFR2(Flk-1/KDR), are relevant in the growth of neurogenic sarcomas. First, VEGF expression was evaluated by Northern blot and immunohistochemical analysis from a spectrum of human peripheral nerve tumors (PNTs) representing varying degrees of malignancy, and compared to tumor vascularity. Compared to a normal nerve, VEGF expression was significantly elevated in both Neurofibromatosis (NF)-1(11.6X) and non-NF-1(7.5X) neurogenic sarcomas, and correlated with increased vascularity (90-131 vessels/HPF). In contrast, VEGF expression in benign PNTs (0.1-1.7X) and accompanying vascularity (14 vessels/HPF) were low.
To determine the functional relevance of VEGF mediated tumor angiogenesis in neurogenic sarcomas, a subcutaneous NF-1 neurogenic sarcoma xenograft model in NOD-SCID mice was developed. VEGFR2 activation was inhibited with the small molecule inhibitor SU5416(SUGEN Inc.), with evaluation of tumor burden, tumor vascularity, BrDU labeling and apoptosis (TUNEL).
Daily intraperitoneal SU5416 (25 mg/kg) resulted in 54.8 percent tumor shrinkage (p<0.02), decreased tumor vascularity (61.5±7.2 vs. control 119±10.8 vessels/HPF), decreased tumor proliferation (1.6 percent±0.2 percent vs. 25.4 percent±2.2 percent BrDU labeled cells) and increased apoptosis (33.9 percent±1.2 percent vs. 1.7 percent±0.01 percent TUNEL positive cells).
These results demonstrate that grade of human PNTs correlate to tumor angiogenesis and VEGF expression. Hence, strategies to inhibit VEGF mediated tumor angiogenesis may be of therapeutic benefit in controlling local growth and metastasis of human neurogenic sarcomas.
1997 Research Fellow:Amy B. Heimberger,MD, Duke University, Medical Center
Chair:Allan H. Friedman, MD
Sponsor:Darrell D. Bigner, MD
Project Title: Cytotoxic Lymphocyte Response Against Central Nervous System Tumors.
Project Update: Our studies are dedicated to the induction of an immunological response against CNS gliomas. The model system is a spontaneously arising, syngeneic, murine astrocytoma (SMA-560) expressing the mutated epidermal growth factor receptor (EGFRvIII) – a tumor specific antigen. Vaccination with peptides corresponding to the mutant splice junction of the EGFRvIII or heat shock protein (gp96) purified from SMA-560 inhibited subcutaneous glioma growth, failed to have efficacy against intracranial gliomas. However, dendritic cells pulsed with SMA-560 extracts increased median survival >285 percent within animals possessing intracranial gliomas without induction of autoimmunity.
The efficacious response is both cytotoxic and humorally mediated. Dendritic cells obtained from glioma patients are phenotypically and functionally normal, thereby making dendritic cell therapy a new and exciting therapeutic intervention for glioma patients.
1998 Rhone-Poulenc Rorer Young Clinician Investigator:Frederick F. Lang, MD, University of Texas MD
Anderson Cancer Center
Chair and Sponsor:
Raymond Sawaya, MD
Project Title: Adenovirus-mediated p53 Gene Transfer Combined With Ionizing Radiation and Antineoplastic Agents Against Wild-type p53 Human Gliomas.Project Update: We are examining adenovirus-mediated p53 gene transfer (Ad-p53) as a treatment for human gliomas. Initial studies demonstrated that unlike mutant-p53 gliomas, wild-type (wt) p53 gliomas are resistant to Ad-p53. To overcome this resistance, we combined Ad-p53 with DNA damaging agents.
To date, we have demonstrated that Ad-p53 sensitizes wt-p53 gliomas to IR in vitro by increasing apoptosis. Additionally, Ad-p53 plus IR significantly attenuates the growth of wt-p53 glioma xenografts implanted in nude mice.
This radiosensitization is dependent on the ability of p53 to bind DNA, but is not solely dependent on exogenous p53 levels. Because Ad-p53 does not radiosensitize normal astrocytes, this combination may be clinically efficacious. Similar results are seen when Ad-p53 is combined with cisplatnin.
1998 Shirley L. Bagan Young Clinical Investigator:, Carl Lauryssen, MD, Washington University, (St Louis)
Chair:Ralph G. Dacey, Jr.,MD
Sponsor:Jack R. Engsberg, MD
Project Title: A Computer Analysis Outcome Study of Cervical Spondylotic Myelopathy.
Project Update:The goal of the study is to objectively evaluate the outcomes of surgically-treated patients with cervical spondylotic myelopathy. Thus far, eight patients with signal change by MRI and five patients without have been enrolled, prospectively. Although the results are encouraging, the final analyses are not complete and enrollment continues.