Abstract 4190: Evaluation of targeted therapy of an experimental glioma model using functional imaging

Abstract

Abstract Genetically engineered mouse models combined with noninvasive functional imaging provide unique opportunities to evaluate molecularly targeted agents. To this end, we evaluated the effectiveness of targeted agents against the Ntv-a PtenloxP/loxp/Ink4a-Arf−/−RCAS/PDGF(+)/Cre(+) genetically engineered mouse glioma model. Agents targeting Akt (perifosine) and mTOR (CCI-779) were evaluated alone and in combination for their therapeutic effectiveness. Therapeutic efficacy was quantified using diffusion weighted magnetic resonance imaging (DW-MRI) and contrast-enhanced MRI to assess changes in tumor cellularity and growth rate, respectively. MRI scans were performed daily for the first week then every second day until the animals expired or become moribund in which case the animals were sacrificed. Two animals from each group were sacrificed for histological analysis of the tumors 24 hours following the final day of treatment using H&E, PCNA, pS6RP and TUNEL. Over the course of the study, CCI-779 treated animals either alone or in combination had statistically smaller tumor volumes versus controls. Tumors treated with perifosine alone were found to be statistically smaller than controls at day 5 but larger than CCI-779 alone and in combination at days 4 and 3, respectively. No difference was observed in tumor volumes between CCI-779 treatment alone or in combination. A 10-15% increase in tumor diffusion values were observed in perifosine and CCI-779 groups on days 3-6 post-treatment initiation. The combination therapy produced a 25-35% increased in tumor ADC values over this same time frame indicating that while each individual therapy provided some level of cell death, the combination was more effective. PCNA stains revealed a decrease in proliferation for perifosine treated tumors with a more profound decrease seen in CCI-779 and in the combination treatment group. Down regulation of the oncogenic signaling molecule pS6RP which is located downstream of mTOR and Ras was observed slightly for perifosine and nearly completely for the CCI-779 and combination treatment groups. Finally, TUNEL staining for the presence of apoptosis revealed slight positivity for perifosine and CCI-779, however, the combination treatment group appeared to have more TUNEL positivity than the other treatment groups. Improvement in overall survival was observed for all treatment groups versus control. Between treatments, CCI-779 and combination therapy were found to have a significant improvement in survival over perifosine. In conclusion, inhibition of mTor and Akt was found to elicit potent antitumor activity alone and were found to be more efficacious in combination. Finally, changes in tumor diffusion values as quantified using DW-MRI appeared to correlate and predict treatment effectiveness and may be useful as a molecular imaging biomarker for clinical translation of targeted agents for brain tumor trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4190.