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Galunisertib promotes bevacizumab-induced vascular normalization in nasopharyngeal carcinoma: Multi-parameter MRI
Jing Yu1, Xia Du1, Shuai Zhang1
1Department of Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.
Abstract:
Tumor vascular normalization (TVN) is associated with antitumor therapeutic efficacy in nasopharyngeal carcinoma (NPC). However, the short time window of TVN is the biggest hindrance to its wide clinical application. We investigated whether targeting transforming growth factor beta can enhance the TVN effect of bevacizumab (BEV)-induced patient-derived xenograft (PDX) models of NPC. We constructed mouse subcutaneous PDX models of NPC and classified the mice into four drug-treatment groups, namely placebo control, galunisertib, BEV, and galunisertib + BEV. We performed MRI multi-parameter examinations at different time points and evaluated the vascular density, vascular structure, and tumor hypoxia microenvironment by histopathology. The efficacy of chemotherapy and drug delivery was evaluated by administering cisplatin. We found that combined therapy with galunisertib and BEV significantly delayed tumor growth, enhanced the TVN effect, and improved chemotherapeutic efficacy compared with monotherapy. Mechanistically, galunisertib reversed the epithelial-mesenchymal transition process and inhibited the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor by downregulating LAMC2. Correlation analysis of MRI data and pathological indicators showed that there was a good correlation between them.
Insights
Combining galunisertib with bevacizumab (BEV) enhances tumor vascular normalization (TVN) in nasopharyngeal carcinoma (NPC) models. This combination therapy improves chemotherapy efficacy by targeting TGF-β signaling and reducing tumor hypoxia.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Tumor vascular normalization (TVN) enhances antitumor efficacy in nasopharyngeal carcinoma (NPC).
- The transient nature of TVN limits its clinical utility.
- Bevacizumab (BEV) is a known agent for inducing TVN.
Purpose of the Study:
- To investigate if targeting transforming growth factor beta (TGF-β) can prolong and enhance the TVN effect of bevacizumab (BEV) in nasopharyngeal carcinoma (NPC) patient-derived xenograft (PDX) models.
- To evaluate the combined therapeutic effects of galunisertib and BEV on NPC growth and response to chemotherapy.
Main Methods:
- Subcutaneous NPC PDX mouse models were established and divided into placebo, galunisertib, BEV, and combination groups.
- Multi-parameter MRI and histopathology were used to assess vascular density, structure, and tumor hypoxia.
- Chemotherapeutic efficacy and drug delivery were evaluated using cisplatin.
Main Results:
- Combined galunisertib and BEV therapy significantly inhibited tumor growth compared to monotherapy.
- The combination treatment demonstrated enhanced TVN and improved chemotherapeutic efficacy.
- Mechanistically, galunisertib reversed epithelial-mesenchymal transition, inhibited HIF-1α and VEGF expression by downregulating LAMC2.
- MRI data correlated well with pathological indicators.
Conclusions:
- Targeting TGF-β with galunisertib can enhance BEV-induced TVN in NPC models.
- Combination therapy offers a promising strategy to overcome the limitations of TVN duration and improve treatment outcomes in NPC.
- This approach warrants further clinical investigation for NPC treatment.
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