Chemoprevention of Gliomas using Nitrones with Anti-c-Met Activity

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DESCRIPTION (provided by applicant): This project is focused on establishing the mechanism of alpha-phenyl-tert-butyl nitrone (PBN), in its ability to inhibit glioma formation in experimental rodent models that vary in tumor grade. We have promising preliminary data that clearly demonstrates that PBN can potentially be an effective anti-tumor agent in vivo, prior to tumor implantation, or once a tumor has formed. Our hypothesis is that c-Met, a tyrosine kinase receptor for the hepatocyte growth factor (scatter factor) plays an integral role in the formation of malignant gliomas, and that altered c-Met levels from PBN treatment suppresses glioma formation. Important hallmarks of malignant gliomas include their invasive behavior and angiogenesis. c-Met is thought to be a mediator in many of the processes of malignant brain tumor progression, including cell proliferation, cell invasion, apoptosis and angiogenesis. Approximately 15,000 patients in the U.S.A. die with glioblastomas per year. Due to the infiltrative nature of gliomas, surgery is rarely effective. Despite modern diagnostics and treatments the median survival time for patients with glioblastomas does not exceed 15 months. A potential chemo-preventative agent that can suppress glioma growth or even eradicate gliomas entirely would be of tremendous benefit to patients that develop malignant tumors. In vivo magnetic resonance (MR) methods are ideally suited to follow changes in tumor growth, angiogenesis, as well as the assessment of c- Met levels which can be used as a marker for predicting the prognosis of gliomas. We currently use non-invasive in vivo MR imaging (MRI) methods to detect tumor morphology, tumor vasculature or angiogenesis (using MR angiography (MRA)), and have preliminary data on c-Met expression (using molecular-targeted MRI). In addition we use molecular biology methods (Western blots, immunofluorescence histology) and histological tumor grading, to correlate with MR imaging, angiography and molecular targeted data. This project will assess PBN in its ability to prevent malignant glioma formation and development, use c-Met knockdown glioma cell clones, and incorporate novel in vivo molecular-targeted MRI techniques for in vivo detection of c-Met in intracranial rat gliomas varying in tumor grades. Intracerebral implantation of rat C6 (forming grade II or III tumors) or RG2 (forming more aggressive grade III or IV tumors) glioma cells will be used in Fisher 344 rats as the glioma models. Specific aim 1 will be to assess the levels of c-Met in the 2 glioma models (C6 and RG2); specific aim 2 will be to establish the effectiveness of PBN as a c-Met suppressor in preventing glioma growth and formation, and to use c-Met knockdown glioma models to further elucidate the role of c-Met in glioma formation; and specific aim 3 will be to develop and validate improved MRI methods for in vivo detection of c-Met expression. There are very few existing agents that are currently applicable for the intervention of malignant gliomas. Other promising characteristics of PBN, in addition to c-Met suppression, are that it is orally bio-available, and it is able to cross the blood-brain-barrier (BBB). PBN seems to be a promising candidate in its ability to be an effective agent against glioma formation, and may be useful as a chemo-preventative agent against glioblastoma multiforme in humans. We have preliminary data that PBN (alpha-phenyl-tert-butyl nitrone) seems to be a promising candidate in its ability to be an effective agent against glioma formation, and may be useful as a chemo-preventative agent against glioblastoma multiforme in humans. Our hypothesis is that c-Met, a tyrosine kinase receptor, plays an integral role in the formation of malignant gliomas, and that PBN is able to decrease c-Met levels, resulting in the suppression of glioma formation. This project will assess PBN in its ability to prevent malignant glioma formation and development, use c-Met knockdown glioma cell clones to elucidate the role of c-Met, and incorporate novel in vivo moleculartargeted MRI (magnetic resonance imaging) techniques for in vivo detection of c-Met in intracranial rat gliomas varying in tumor grades.