Rationale:
Tumor vascular normalization (TVN) is emerging to enhance the efficacy of anticancer treatment in many
cancers including
glioblastoma (GBM). However, a common and severe challenge being currently faced is the transient TVN effect, hampering the sustained administration of anticancer
therapy during TVN window. Additionally, the lack of non-
contrast agent-based imaging
biomarkers to monitor TVN process postpones the clinical translation of TVN strategy. In this study, we investigated whether dual inhibition of
VEGF and the glycolytic activator PFKFB3 could reinforce the TVN effect in GBM. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) and intravoxel incoherent motion (IVIM)-MRI were performed to monitor TVN process and to identify whether IVIM-MRI is a candidate or complementary imaging
biomarker for monitoring TVN window without exogenous
contrast agent administration. Methods: Patient-derived orthotopic GBM xenografts in mice were established and treated with
bevacizumab (BEV), 3PO (PFKFB3 inhibitor), BEV+3PO dual
therapy, or saline. The vascular morphology, tumor hypoxia, and
lactate level were evaluated before and at different time points
after treatments.
Doxorubicin was used to evaluate chemotherapeutic efficacy and drug delivery. Microarray of angiogenesis
cytokines and western blotting were conducted to characterize post-treatment molecular profiling. TVN process was monitored by DCE- and IVIM-MRI. Correlation analysis of pathological indicators and MRI parameters was further analyzed. Results: Dual
therapy extended survival and delayed
tumor growth over each
therapy alone, concomitant with a decrease of cell proliferation and an increase of cell apoptosis. The dual
therapy reinforces TVN effect, thereby alleviating tumor hypoxia, reducing
lactate production, and improving the efficacy and delivery of
doxorubicin. Mechanistically, several angiogenic
cytokines and pathways were downregulated after dual
therapy. Notably, dual
therapy inhibited Tie1 expression, the key regulator of TVN, in both endothelial cells and
tumor cells. DCE- and IVIM-MRI data showed that dual
therapy induced a more homogenous and prominent TVN effect characterized by improved vascular function in
tumor core and
tumor rim. Correlation analysis revealed that IVIM-MRI parameter D* had better correlations with TVN pathological indicators compared with the DCE-MRI parameter Ktrans. Conclusions: Our results propose a rationale to overcome the current limitation of BEV monotherapy by integrating the synergistic effects of
VEGF and PFKFB3 blockade to enhance
chemotherapy efficacy through a sustained TVN effect. Moreover, we unveil IVIM-MRI parameter D* has much potential as a complementary imaging
biomarker to monitor TVN window more precisely without exogenous
contrast agent injection.