This application outlines a pre-clinical therapeutic approach for controlling the infiltration of malignant glioma cells in a novel intracranial xenograft model. Since it is the regional and distant infiltration of malignant glioma cells into adjacent peritumoral normal brain which confounds local therapy of primary brain tumors clinically, we have modeled this process in vitro and in vivo and seek to define the molecular basis for the invasive phenotype. Carboxyamido-triazole (CAI), identified initially by its anti-motility effect, inhibits G-protein mediated signal transduction via its effect on non-voltage-gated calcium channels. This signal transduction pathway is common to signalling involved in protease secretion, growth and motility factor expression and angiogenesis. It is an agent which is orally bioavailable, very limited in its toxicity and novel in its effect. We have used CAI in 2 models of glioma invasion in vitro and found impressive anti-invasive effects in the absence of significant cytotoxicity. This project is designed to confirm the brain delivery of CAI in an animal model of human glioma and to demonstrate its efficacy as an anti-invasive agent in this system. We will compare tumor growth and infiltration in animals treated daily with oral CAI for 4 weeks following the establishment of intracranial xenografts and follow a cohort of animals for non-invasive assessment of tumor growth and survival. Neuropharmacologic HPLC data will be generated and observation of the molecular mechanism of action of CAI will be made by staining for the protease enzymes and extracellular matrix molecules involved in the process of glioma invasion. Non-invasive magnetic resonance imaging (MRI) will be employed to serially examine tumor growth and infiltration in animals without their sacrifice, a technique which will be used clinically. Our work in this project will lay the groundwork for direct translation to clinical trials in human glioma patients. The effective control of tumor invasion will complement local cytoreductive therapeutic approaches to allow sustained tumor control and improved outcomes in patients with malignant gliomas.
| Ge, S; Rempel, S A; Divine, G et al. (2000) Carboxyamido-triazole induces apoptosis in bovine aortic endothelial and human glioma cells. Clin Cancer Res 6:1248-54 |
