Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

• Published in: The Journal of clinical investigation 2017-10, Vol.127 (10), p.3689-3701
• Main Authors: Chen, Minfeng, Lei, Xueping, Shi, Changzheng, Huang, Maohua, Li, Xiaobo, Wu, Baojian, Li, Zhengqiu, Han, Weili, Du, Bin, Hu, Jianyang, Nie, Qiulin, Mai, Weiqian, Ma, Nan, Xu, Nanhui, Zhang, Xinyi, Fan, Chunlin, Hong, Aihua, Xia, Minghan, Luo, Liangping, Ma, Ande, Li, Hongsheng, Yu, Qiang, Chen, Heru, Zhang, Dongmei, Ye, Wencai
• Format: Article
• Language: English
• Subjects: A549 Cells; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; BALB 3T3 Cells; Biomedical research; Blood vessels; Cancer therapies; Cytoskeleton; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - drug effects; Endothelial cells; Enzymes; Fibroblast activation protein; Fibroblasts; Gangrene; Gelatinases - biosynthesis; HeLa Cells; Hep G2 Cells; Humans; Membrane Proteins - biosynthesis; Metastasis; Mice; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Observations; Pericytes; Prodrugs - pharmacology; Prostate; Serine Endopeptidases - biosynthesis; Toxicity; Treatment resistance; Tubulin; Tumors; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI94258

Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.