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Downloaded from clincancerres.aacrjournals.org on September 15, 2014. 2007 American Association for
Cancer Research.
Abstract
Purpose: The median survival for patients diagnosed with glioblastoma multiforme, the most
common type of brain tumor, is less than 1 year. Animal glioma models that are more predictive
of therapeutic response in human patients than traditional models and that are genetically and
histologically accurate are an unmet need. The nestin tv-a (Ntv-a) genetically engineered mouse
spontaneously develops glioma when infected with ALV-A expressing platelet-derived growth
factor, resulting in autocrine platelet-derived growth factor signaling.
Experimental Design: In the Ntv-a genetically engineered mouse model, T2-weighted and
T1-weighted, contrast-enhanced magnetic resonance images were correlated with histology,
glioma grade (high or low), and survival. Magnetic resonance imaging (MRI) was therefore used
to enroll mice with high-grade gliomas into a second study that tested efficacy of the current
standard of care for glioma, temozolomide (100 mg/kg qdx5 i.p., n = 13).
Results: The Ntv-a model generated a heterogeneous group of gliomas, some with high-grade
growth rate and histologic characteristics and others with characteristics of lower-grade gliomas.
We showed that MRI could be used to predict tumor grade and survival. Temozolomide treatment
of high-grade tv-a gliomas provided a 14-day growth delay compared with vehicle controls.
Diffusion MRI measurement of the apparent diffusion coefficient showed an early decrease in
cellularity with temozolomide, similar to that observed in humans.
Conclusions: The use of MRI in the Ntv-a model allows determination of glioma grade
and survival prediction, distribution of mice with specific tumor types into preclinical trials,
and efficacy determination both by tumor growth and early apparent diffusion coefficient
response.
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Results
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Low-grade
glioma
High-grade
glioma
22/37
11 F 28
20 F 2
13/37
31 F 7
10 F 1
8F2
84 F 2
158
84 F 2
54
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Cancer Research.
Fig. 2. A, example of T1-weighted post-contrast MRI time courses for high-grade glioma. Low-grade tumors did not enhance and are not shown. B, mean enhancing
volume for high-grade Ntv-a glioma. The enhancing volume of high-grade tumors increased at a rate exceeding tumor growth (see Fig. 1D). The enhancing fraction of
the tumor, therefore, increased with tumor growth, indicating aggressive vascular development. C, example of late-stageT1-weighted post-contrast MRI, in which the
contrast-enhancing volume exceeded 50% of the total tumor volume. For late-stage, high-grade tumors, the mean proportion of the contrast-enhancing volume increased
from 20% to 50%. D, example of a ring-enhancement pattern on aT1-weighted post-contrast MRI, typical of contrast-enhancing behavior of high-grade human glioblastoma.
T1w, T1weighted; T2w,T2 weighted.
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Discussion
RCAS/tv-a based GEM glioma models represent an opportunity for studying correlates between histology and imaging
characteristics and for developing and testing of new therapeutic
strategies for this disease. We characterized tumor development
characteristics of PDGF-induced Ntv-a gliomas using a multimodal MRI approach and quantified the response of GEM
gliomas to temozolomide, the current standard of care
chemotherapy for gliomas in humans.
Infection of Ntv-a mice with RCAS-PDGF viral vectors
encoding PDGF resulted in glioma formation in 80% of
animals that could be classified as high or low grade using
MRI at 4 to 5 weeks of age. High-grade tumors, defined by
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Fig. 5. A, tumor growth time course shown for vehicle control (n = 12) and temozolomide (qdx5 100 mg/kg i.p.) treated high-grade gliomas. B, corresponding ADC time
course for the vehicle control and treated animals. A significant early increase in ADC was observed in the treated group, which corresponded to significant growth inhibition,
compared with the control group. The treated group ADC continued to increase until it reached a maximum at 52 d, at which time there was sharp decrease in ADC, and
tumor progression was observed. C, survival plot for temozolomide and control groups. Median survival was 52 d for the control group versus 70 d for the treatment group.
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