SHS_571003 COBC FNIH 13102
The Role of Cidofovir and Structural Analogs as Adjuvant Therapy for Glioblastoma
This project is designed to improve outcomes for brain tumor patients by establishing that Cidofovir and/or its analogs, when combined with radiation therapy, is more effective in treating GBM than is current standard-of-care treatment for this cancer. Recently, antiviral therapies aimed at human cytomegalovirus (HCMV) have demonstrated efficacy in patients with glioblastoma (GBM). We have determined that Cidofovir (CDV), an FDA approved antiviral agent for CMV infection, potently inhibits GBM proliferation both in vitro and in an intracranial xenograft mouse model of primary GBM. Furthermore, our investigations of CDV have indicated that, while the antiviral effect is significant to the antitumr response, CDV possesses potent antitumor properties even in the absence of CMV infection. In Aim 1, we plan to use existing mouse xenograft models developed by our co-investigator Dr. David James at UCSF to optimize treatments based on acquired knowledge of investigational agent pharmacokinetics and to determine optimal regimens to use when combining inhibitors with radiation theraphy. In Aim 2 we will use co-investigator Dr. Nino Chiocca's transgenic mouse model of spontaneously occurring glooms +/- CMV infection to understand the impact of antiviral therapy in the setting of CMV-mediated GBM tumor genesis. In addition, we will examine the impact of antiviral therapy with respect to the influence of CMV on the tumor microenvironment and host immune response to tumor. Finally, in Aim 3 we plan to investigate the mechanisms by which CDV and CDV-derived compounds elicit DNA damage and interfere with DNA repair mechanisms. We anticipate that one of the major advantages of these compounds will be their high therapeutic index: i.e., limited toxicity in normal cells, but dramati apoptotic pathway activation and prevention of DNA repair in tumor cells, which could significantly delay or possibly prevent radiation and chemo-resistance critical for GBM recurrence.
Charles Cobbs, M.D.
NIH (National Institutes of Health)