Theranostics 2020; 10(16):7245-7259. doi:10.7150/thno.44427 This issue Cite

Research Paper

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

Junfeng Zhang1*, Wei Xue1*, Kai Xu1, Liang Yi2, Yu Guo1, Tian Xie1, Haipeng Tong1, Bo Zhou1, Shunan Wang1, Qing Li3, Heng Liu4, Xiao Chen5, Jingqin Fang1, Weiguo Zhang1,6✉

1. Department of Radiology, Daping Hospital, Army Medical University, Chongqing, 400042, China.
2. Department of Neurosurgery, Daping Hospital, Army Medical University, Chongqing, 400042, China.
3. Department of Oncology, Daping Hospital, Army Medical University, Chongqing, 400042, China.
4. Department of Radiology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China.
5. Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China.
6. Chongqing Clinical Research Center of Imaging and Nuclear Medicine, Chongqing, 400042, China.
*These authors contributed equally to this work.

Citation:
Zhang J, Xue W, Xu K, Yi L, Guo Y, Xie T, Tong H, Zhou B, Wang S, Li Q, Liu H, Chen X, Fang J, Zhang W. Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: insights from protein expression profiling and MRI. Theranostics 2020; 10(16):7245-7259. doi:10.7150/thno.44427. https://www.thno.org/v10p7245.htm
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Abstract

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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.

Keywords: glioblastoma, tumor vascular normalization, PFKFB3, bevacizumab, MRI


Citation styles

APA
Zhang, J., Xue, W., Xu, K., Yi, L., Guo, Y., Xie, T., Tong, H., Zhou, B., Wang, S., Li, Q., Liu, H., Chen, X., Fang, J., Zhang, W. (2020). Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: insights from protein expression profiling and MRI. Theranostics, 10(16), 7245-7259. https://doi.org/10.7150/thno.44427.

ACS
Zhang, J.; Xue, W.; Xu, K.; Yi, L.; Guo, Y.; Xie, T.; Tong, H.; Zhou, B.; Wang, S.; Li, Q.; Liu, H.; Chen, X.; Fang, J.; Zhang, W. Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: insights from protein expression profiling and MRI. Theranostics 2020, 10 (16), 7245-7259. DOI: 10.7150/thno.44427.

NLM
Zhang J, Xue W, Xu K, Yi L, Guo Y, Xie T, Tong H, Zhou B, Wang S, Li Q, Liu H, Chen X, Fang J, Zhang W. Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: insights from protein expression profiling and MRI. Theranostics 2020; 10(16):7245-7259. doi:10.7150/thno.44427. https://www.thno.org/v10p7245.htm

CSE
Zhang J, Xue W, Xu K, Yi L, Guo Y, Xie T, Tong H, Zhou B, Wang S, Li Q, Liu H, Chen X, Fang J, Zhang W. 2020. Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: insights from protein expression profiling and MRI. Theranostics. 10(16):7245-7259.

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