A primary cause for failure in the management of patients with glial neoplasms is recurrence after surgery due to prior invasion of these tumor cells into brain parenchyma. Despite aggressive efforts, very little progress has been made over the last two decades towards extending survival for patients with malignant gliomas. Of considerable importance to improvements in management of patients with gliomas is the availability of an adequate animal model. Optimally, this system would embody anatomical, clinical, histopathological and molecular features concordant with those of the spontaneous human disease. The applicants have already developed tumorigenic cell lines from spontaneously arising canine astrocytomas. A technique has been invented, tested and patented by which fetal immune tolerance to these allogenic glioma cells can be induced in dogs. Such dogs accept orthotopic implants of the allogenic glioma cells, and subsequently develop intracranial tumors with histopathological features similar to human and canine spontaneous gliomas. The model is in need of further refinements that would increase its success rate, as well as studies to define the clinical endpoints that would establish the model as a reference for experimental neuro-oncology: surgical resection, magnetic resonance imaging (MRI) studies of growth properties, molecular genetic analysis of oncogenes and tumor suppressor genes, and initial tumor response to current chemotherapy and radiation regimens. Such a model would be of use to researchers approaching new brain tumor therapy from the disciplines of surgery, chemotherapy, radiation therapy, gene therapy, antiangiogenesis, immunology, and other disciplines.
The Specific Aims of the project are: 1) Optimize the success rate for induction of immune tolerance to allogenic glioma cells; 2) Characterize the clinical course of dogs with brain tumors, and assess whether different canine glioma cell lines produce tumors with clinicopathological features concurrent with spontaneous human or canine gliomas; and 3) Evaluate the response to conventional therapy of the allogenic canine glioma, including surgical resection, radiation, and chemotherapy.
