Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents
Minfeng Chen, … , Dongmei Zhang, Wencai Ye
Minfeng Chen, … , Dongmei Zhang, Wencai Ye
Published August 28, 2017
Citation Information: J Clin Invest. 2017;127(10):3689-3701. https://doi.org/10.1172/JCI94258.
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Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Abstract

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.

Authors

Minfeng Chen, Xueping Lei, Changzheng Shi, Maohua Huang, Xiaobo Li, Baojian Wu, Zhengqiu Li, Weili Han, Bin Du, Jianyang Hu, Qiulin Nie, Weiqian Mai, Nan Ma, Nanhui Xu, Xinyi Zhang, Chunlin Fan, Aihua Hong, Minghan Xia, Liangping Luo, Ande Ma, Hongsheng Li, Qiang Yu, Heru Chen, Dongmei Zhang, Wencai Ye

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Figure 6

Antitumor effect of Z-GP-DAVLBH in multiple tumor xenografts.

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Antitumor effect of Z-GP-DAVLBH in multiple tumor xenografts. (A) Compar...
(A) Comparative therapeutic efficacy of VLB, DAVLBH, Z-GP-DAVLBH, and Boc-AP-DAVLBH in MDA-MB-231 xenografts. Mice bearing MDA-MB-231 xenografts received an i.v. injection of saline (containing 1% DMSO), VLB, DAVLBH, Z-GP-DAVLBH, or Boc-AP-DAVLBH once every other day for 14 days. Each curve represents the growth of a single tumor in an individual mouse. The dotted vertical lines denote the final day of dosing. (B) Detection of the anticancer spectrum of Z-GP-DAVLBH. Mice bearing HepG2 xenografts (n = 5), A549 xenografts (n = 5), HeLa xenografts (n = 5), CNE-2 xenografts (n = 6), invasive ductal carcinoma patient-derived xenografts (PDX, n = 5), and hepatocellular carcinoma PDX (n = 5) received an i.v. injection of Z-GP-DAVLBH (2.0 μmol/kg) once every other day for 12 or 14 days. Mice in the vehicle group received saline (containing 1% DMSO) only. (C and D) The antitumor effects of Z-GP-DAVLBH in the large MDA-MB-231 tumor experiment. Mice bearing MDA-MB-231 xenografts received 2.0 μmol/kg i.v. injection of Z-GP-DAVLBH or saline containing 1% DMSO once every other day for 16 or 32 days, until the tumor volume reached approximately (C) 750 mm3 (n = 5) or (D) 2,500 mm3 (n = 5). For B–D, the tumor volume (left) and the tumor weight (right) are shown. The results are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 versus the vehicle group based on a 2-tailed unpaired t test.