Prognosis remains extremely poor for
malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and
proteasome inhibition strategies, have not resulted in sustained anti-
glioma clinical efficacy. We tested the anti-
glioma efficacy of the anti-angiogenic
receptor tyrosine kinase inhibitor
cediranib and the novel
proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse
glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of
tumor growth. While single agent
cediranib or
SC68896 treatment did not alter
tumor growth or survival, combined
cediranib/
SC68896 significantly delayed
tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased
tumor necrosis in the
cediranib/
SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined
cediranib/
SC68896 group versus untreated. Consistent with our previous findings,
cediranib alone did not significantly alter mean
tumor rCBF, rCBV, rMTT, or Ktrans. In contrast,
SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined
cediranib/
SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined
cediranib/
SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the combination of
cediranib with a
proteasome inhibitor substantially increases the anti-angiogenic efficacy produced from either agent alone, and synergistically slows
glioma tumor growth and extends survival, suggesting a promising treatment which warrants further investigation.