Targeted MV-CEA as a novel anti-tumor agent against gliomas
Our group has developed a novel potent anti-tumor approach to attack recurrent gliomas, by utilizing an Edmonston’s vaccine strain of measles virus, which is engineered to produce the marker peptide CEA (MV-CEA). CEA serves as a trackable marker of viral gene expression and can be used to monitor viral therapy in vivo. Using MV-CEA we have demonstrated significant antitumor activity in vitro against several glioma lines and in vivo in subcutaneous and orthotopic glioma xenografts. We now propose to perform additional preclinical work in order to optimize MV-CEA-based therapy for the treatment of recurrent gliomas.
In order to overcome challenges associated with the variability of expression of the measles virus receptor CD46 in gliomas and the ubiquitous, although low level, expression of CD46 in normal brain, we propose to exploit alterations of the EGFR pathway, possibly in combination with ablation of the natural binding to the CD46 and SLAM receptors to construct retargeted MV-CEA derivatives. These will be comparatively tested in vitro and in vivo in order to decide on the optimal candidate for clinical translation.
This proposal brings forward two novel concepts: exploring the use of an attenuated measles virus of the Edmonston vaccine lineage to treat recurrent gliomas and use of a novel tracking system that could significantly improve our ability to monitor virotherapy trials in brain tumors. Our hypothesis is that targeted MV-CEA derivatives will be potent antitumor agents against glioblastoma multiforme with a superior efficacy/toxicity profile as compared to MV-CEA.
Therefore, our proposal has the following specific aims:
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