Abstract 5281: Gemcitabine is evaluated as an alternative treatment to temozolomide for high grade gliomas
Authors: Galbán Stefanie , Lemasson Benjamin , Williams Terence M. , Li Fei , Heist Kevin , Johnson Timothy D. , Rehemtulla Alnawaz , Galban Craig , Ross Brian D. 
Published: June 2012

Glioblastoma multiforme (GBM) remains a challenging malignancy due to intrinsic resistance to therapy. Pre-clinical mouse models which recapitulate the human disease provide an opportunity to identify and test novel agents that could be used alone or in combination with other systemic agents and/or radiation therapy. Here we describe the use of a genetically engineered murine GBM model [Ink4a-Arf-/- PtenloxP/loxp/ Ntv-a RCAS/PDGF(+)/Cre(+)] and functional magnetic resonance imaging (MRI) to evaluate systemic agents alone or in combination with radiation. The current standard therapy for patients bearing GBMs is Temozolomide (TMZ) combined with radiation yet recent analysis of O-6-methylguanine-DNA methyltransferase (MGMT) status in GBMs has linked unmethylated MGMT promoter with poor outcome. Thus we evaluated Gemcitabine (GEM) as a novel therapy for GBM concurrent with radiation and compared it to standard therapy. GEM, a deoxycytidine analog, is a potent radiosensitizer that demonstrates cytotoxic, anti-clonogenic, and radiosensitizing effects in GBM cell lines.

Therapeutic efficacy was quantified by contrast-enhanced MRI and diffusion-weighted MRI (DW-MRI) for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ or radiation alone showed a significant reduction in tumor volume compared to control mice as early as three days post treatment start. Both combined treatment (GEM+IR and TMZ+IR) resulted in improved effectiveness over single therapies. A significant reduction in tumor volume compared to GEM, TMZ or IR groups was observed. Furthermore, both combination therapies significantly prolonged survival compared to the other groups as early as day 7 after start of treatment. There was no significant difference between both combined treatments either in tumor growth or in survival. ADC values were found to increase immediately upon administration of GEM in both alone and combination therapies. In contrast, a gradual increase in ADC values was observed in tumors treated with IR and TMZ, both alone and in combination.GEM concurrent with radiation resulted in significant reduction in tumor volume and prolonged survival in this clinically-relevant GBM mouse model. GEM combined with radiation had the same effect GBM as compared to TMZ combined with radiation. We also demonstrated the successful implementation of an imaging biomarker surrogate (ADC) which correlated with efficacy. Ink4a-Arf-/- PtenloxP/loxP/ Ntv-a RCAS/PDGF(+)/Cre(+) mice serve as a valuable pre-clinical GBM model with the potential to identify novel therapeutics for early phase I/II testing for GBM patients. Based on these results, GEM combined with IR appears to be a suitable alternative to treat tumors that have a poor response to traditional therapies (eg. unmethylated MGMT).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5281. doi:10.1158/1538-7445.AM2011-5281