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• W2007510144 abstract "Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCNGR-TNF is a novel peptide-targeted agent coupling CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumor necrosis factor alpha (TNF), presently in clinical development (phase II clinical studies in MPM, HCC and CRC). To further elucidate its mechanism of action, we investigated the NGR-TNF homing and downstream effects obtained with doses comparable to those used in clinical trials. Targeting studies carried-out using NGR-quantum dots (-Qd) administered in vivo demonstrate that the binding to CD13 occurs only in neo-angiogenic tissues, including tumor vessels, sparing CD13-expressing normal tissues. The specificity of this binding is due to the expression of an NGR-binding complex containing CD13. Indeed, in vitro RNA-interfering studies with CD13-specific shRNA demonstrate that the expression of CD13 on the target cells is essential but not sufficient for NGR-binding capability. Herein, for the first time, we formally demonstrated the physical interaction between NGR and CD13 on target cell surface by pool-down experiments using NGR-biotinylinated peptides. Although the molecular characterization of determinants responsible for NGR-binding capability is still ongoing, microvesicles released by NGR-binding cells are able to transfer the NGR-binding capability to NGR-non-binder cells, suggesting that the binding complex associates on the target cell before NGR engages CD13. In addition, the in vivo activity of NGR-TNF may be due to the NGR-mediated homing to target cells determining an increase in the affinity for TNF receptor (TNFR), and/or to an NGR-mediated cell signalling via CD13. Our data support the contribution of both mechanisms. First, using a recombinant tagged-human TNF (hTNF-Fc) as a probe along with NGR-TNF and TNF as competitors, NGR-TNF has an NGR-mediated higher affinity for TNFR than TNF. Second, in TNF-activated endothelial cells, NGR-TNF impairs survival signals via the significant inhibition of Mek, Erk1/2, and Akt, and activates apoptotic signals (caspases 3, 8 and 9) that induce apoptosis of tumor vessel endothelial cells in vivo. Of note, these pathways are similarly activated also using NGR and TNF as separate molecules engaging CD13 and TNFR, respectively, indicating that both NGR and TNF portions contribute to the activation of signaling pathways by NGR-TNF. In conclusion, the binding of NGR to CD13 determines not only the “mere homing” of NGR-TNF but also a) the stabilization of the NGR-CD13/TNF-TNFR interaction and b) a direct effect of CD13, leading to a highly selective homing on tumor blood vessels and apoptosis of angiogenic endothelial cells in vivo, thus significantly contributing to the control of tumor growth.Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 391." @default.
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• W2007510144 date "2010-04-15" @default.
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• W2007510144 title "Abstract 391: Both NGR and TNF portions of NGR-TNF contribute to tumor vessel specific homing and apoptosisin vivo" @default.
• W2007510144 doi "https://doi.org/10.1158/1538-7445.am10-391" @default.
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