Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: insights from protein expression profiling and MRI.

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