Abstract
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.
Highlights
The most lethal primary brain tumors are malignant gliomas
As angiogenesis is a key hallmark of tumor progression in high grade gliomas, it is essential that monitoring changes in the development of neovasculature be incorporated into the assessment of the pathophysiological response to therapy[1, 15] as therapeutic efficacy in glioma is linked to key tumor microenvironment variables such as angiogenesis, drug delivery, the effect of hypoxia on tumor biology, and other critical phenomena, it is important that relevant orthotopic in vivo models are employed to investigate it
The images clearly delineate the tumors in the mouse brains, and indicate a substantially smaller tumor size with combined cediranib/SC68896 treatment compared to single agent or vehicle treatment
Summary
The most lethal primary brain tumors are malignant gliomas. The most common glioma, glioblastoma (World Health Organization [WHO] grade IV) is an aggressive and robustly angiogenic tumor associated with a median survival of only 12–16 months despite improved treatments and surgical approaches.[1,2,3] The limited efficacy of conventional chemotherapeutic agents underscores an urgent need for new therapeutic strategies. In combination with immunohistological studies of necrosis and vascularization, the current study revealed a synergistic efficacy of combined cediranib and SC68896 in malignant glioma in vivo, resulting in enhanced anti-angiogenic effects and increased survival of treated mice. These findings provide a basis for further studies of this novel therapeutic combination in malignant glioma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
