Galunisertib promotes bevacizumab-induced vascular normalization in nasopharyngeal carcinoma: Multi-parameter MRI evaluation

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.