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• W2885672559 abstract "Abstract Chlorotoxin is an established tumor targeting peptide that naturally occurs in scorpion venom. 131I-labelled chlorotoxin assessed in early phase human glioma clinical trials achieved promising results. A peptide drug conjugate (PDC) composed of chlorotoxin peptide linked to a cytotoxic payload (cryptophycin analog) was used as a tool to probe the tumor targeting mechanism of chlorotoxin. The PDC proved efficacious, yet differential sensitivity was observed in multiple human tumor models. Previously described chlorotoxin targets did not align with observed PDC activity; therefore, studies to further elucidate its mechanism were undertaken. PDC treatment of distinct xenograft models led to a wide range of antitumor activity even though similar levels of active metabolite were present in tumor lysates; thus it was hypothesized that a role for chlorotoxin in uptake may be relevant. We identified that the endocytic receptor Neuropilin1 (NRP1) binds to chlorotoxin peptide fragments following proteolytic digestion in vitro. NRP1 binding was selective for peptides with a free C-terminal arginine, while native chlorotoxin which has an amidated C-terminal arginine did not bind. Recovery of chlorotoxin from ex vivo tumor lysate revealed its metabolism to a carboxylated C-terminal arginine version of the peptide, capable of binding to NRP1. These data suggest that chlorotoxin acts as a cryptic peptide incapable of binding to NRP1 systemically and only when metabolized in the tumor microenvironment is NRP1 binding revealed. The expression level of human NRP1 in tumors correlated to the PDC antitumor activity in multiple xenograft models; a wider therapeutic window was observed when NRP1 was highly expressed. Reduction of NRP1 levels in vivo through administration of NRP1 blocking antibodies or by NRP1 knockout in tumor cells blunted PDC antitumor activity while not affecting activity of the cytotoxic payload alone. Reduced PDC antitumor activity correlated with significantly lower levels of active metabolite detected in NRP1-deficient tumors. Together, our findings suggest that chlorotoxin metabolized in the tumor microenvironment binds NRP1 on tumor cells to increase uptake of active metabolite into cells, resulting in enhanced antitumor activity. The identification of NRP1 as an uptake mechanism for chlorotoxin will enable selection of tumors for treatment with chlorotoxin-based therapeutics. Citation Format: Donna Kolber-Simonds, Jiayi Wu, Utpal Majumder, Daniel Custar, Danyang Li, Hong Du, Maarten H. Postema, Thomas Noland, Andrew Hart, George Lai, Sean Eckley, Vaishali Dixit, Karen Tendyke, Kenichi Nomoto, Mary Woodall-Jappe, Sharon McGonigle. Role for neuropilin1 in mode of action of chlorotoxin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3961." @default.
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• W2885672559 date "2018-07-01" @default.
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• W2885672559 title "Abstract 3961: Role for neuropilin1 in mode of action of chlorotoxin" @default.
• W2885672559 doi "https://doi.org/10.1158/1538-7445.am2018-3961" @default.
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