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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 ? (FAP?) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAP?-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 FAP?-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.

SUBMITTER: Chen M

PROVIDER: S-EPMC5617663 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents.

Chen Minfeng M Lei Xueping X Shi Changzheng C Huang Maohua M Li Xiaobo X Wu Baojian B Li Zhengqiu Z Han Weili W Du Bin B Hu Jianyang J Nie Qiulin Q Mai Weiqian W Ma Nan N Xu Nanhui N Zhang Xinyi X Fan Chunlin C Hong Aihua A Xia Minghan M Luo Liangping L Ma Ande A Li Hongsheng H Yu Qiang Q Chen Heru H Zhang Dongmei D Ye Wencai W

The Journal of clinical investigation 20170828 10

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 engineerin ...[more]

PMID: 28846068

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Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents.

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Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents.

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