Junfeng Zhang1 and Weiguo Zhang1
1Radiology, Daping Hospital, Army Medical University, Chongqing, China
Synopsis
Tumor vascular normalization induced by
antiangiogenic therapy such as bevacizumab (BEV) is a promising strategy to
remodel tumor microenvironment. However, this effect is transient and
finally vanished because of inevitable adaptive therapy resistance. In
this study, we found that targeting tumor glycolysis activator PFKFB3 is a
novel potential strategy to enhance BEV therapy efficacy and prolonged vascular
normalization in glioblastoma. IVIM parameters are much better than DCE-MRI as
alternative translatable imaging biomarkers for evaluating tumor response and
monitoring vascular normalization.
Background and Purpose
Tumor vascular normalization induced by antiangiogenic therapy such as bevacizumab(BEV) is a promising strategy to remodel tumor microenvironment, resulting in improved chemotherapeutic sensitivity, efficient drug delivery and active tumor immune response. However, this effect is transient and finally vanished because of inevitable adaptive therapy resistance. The purpose of this study is to investigate whether targeting tumor
glycolysis by PFKFB3 blockade is a novel potential strategy to enhance BEV therapy efficacy and prolonged vascular normalization in glioblastoma(GBM) and to evaluate treatment-related
molecular characterization and clinically translatable MR imaging biomarkers of
tumor response.Materials and Methods
Patient-derived orthotopic GBM xenografts in mice were
established and imaged before and at different time points(day2,day5,day8,day12,day20)
after treatment with bevacizumab(BEV), 3PO(PFKFB3 inhibitor), BEV and 3PO, and
saline. Tumor volume, cellularity, neovascularization, and metabolites were
monitored by T2WI, IVIM, DCE-MRI, and 1H-MRS,
respectively. Pathology, proteome microarray and western blotting were analyzed
to correlate with imaging parameters and evaluate post-treatment molecular
profiling.Results
BEV treatment-induced remarkable PFKFB3
expression with a time-dependent manner compared with control (P<0.05), and
reduced reversely after the addition of 3PO. 3PO treatment enhanced BEV
therapeutic efficacy with significant tumor growth inhibition, concomitant with
a decrease of cell proliferation and augment of cell apoptosis. Multiparametric
MRI and histology analyses revealed that compared with BEV monotherapy, BEV+3PO
dual therapy prolonged and sustained vascular normalization with reduced
vascular permeability and perfusion recovery, improving tumor oxygenate status
and reduced lactate production(P<0.05). BEV monotherapy upregulated
angiogenic cytokines (IL-4, IL-6, CXCL-16 and TIE-1) and activated alternative
pathways(cytokine-cytokine receptor interaction, IL-17 and PI3K-Akt). These
molecules were downregulated after dual therapy(P<0.05). Imaging-histology
correlation analysis shown that IVIM outperformed DCE-MRI for monitoring tumor
therapeutic response. Perfusion fraction f was positively correlated with
microvascular density(r=0.9177) and hypoxia(r=0.5681), and D* was correlated
with vascular maturation(r=0.5884).Conclusions
Targeting PFKFB3 has much potential to synergize
with antiangiogenic therapy by abating tumor glycolysis and remodeling tumor vascular
microenvironment. IVIM parameters are much better than DCE-MRI as alternative translatable
imaging biomarkers for evaluating tumor response and monitoring vascular
normalization without exogenous contrast media.Acknowledgements
We thank Prof. Weiguo Zhang and other colleagues for their generous guidance and support. This work was supported by the National Natural Science Foundation of China (NSFC, No. 81571660 and 81801672)References
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