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      Disrupting tumor onset and growth via selective cell tagging (SeCT) therapy

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          Abstract

          HeLa cancer cells in mice can be tagged in vivo with therapeutic moieties, thereby disrupting either tumor onset or growth.

          Abstract

          This study presents the early framework of selective cell tagging (SeCT) therapy, which is the concept of preferentially labeling specific cells in vivo with chemical moieties that can elicit a therapeutic response. Using glycosylated artificial metalloenzyme (GArM)–based protein labeling, this study reports two separate functional strategies. In one approach, early tumor onset can be suppressed by tagging cancer cells in living mice with an integrin-blocking cyclic–Arg-Gly-Asp (cRGD) moiety, thereby disrupting cell adhesion onto the extracellular matrix. In another approach, tumor growth in mice can be reduced by tagging with a cytotoxic doxorubicin moiety. Subsequent cell death occurs following internalization and drug release. Overall, experiments have shown that mouse populations receiving the mixture of SeCT labeling reagents exhibited a significant delay/reduction in tumor onset and growth compared with controls. Highlighting its adaptability, this work represents a foundational step for further development of SeCT therapy and its potential therapeutic applications.

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          Most cited references41

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          RGD and other recognition sequences for integrins.

          Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.
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            Integrins in cancer: biological implications and therapeutic opportunities.

            The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.
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              Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

              Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                April 2021
                23 April 2021
                : 7
                : 17
                : eabg4038
                Affiliations
                [1 ]Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
                [2 ]GlycoTargeting Research Laboratory, RIKEN Baton Zone Program, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
                [3 ]RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
                [4 ]RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
                [5 ]Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya Street, Kazan 420008, Russia.
                [6 ]School of Advanced Science and Engineering, Department of Chemistry and Biochemistry, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan.
                [7 ]Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan.
                Author notes
                [* ]Corresponding author. Email: kotzenori@ 123456riken.jp
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-8850-5163
                http://orcid.org/0000-0001-9656-5839
                http://orcid.org/0000-0001-9456-2167
                http://orcid.org/0000-0002-9766-6639
                http://orcid.org/0000-0001-5929-2392
                http://orcid.org/0000-0002-2436-7427
                http://orcid.org/0000-0001-6932-4802
                Article
                abg4038
                10.1126/sciadv.abg4038
                8064634
                33893089
                a9648ec6-1cfc-49ee-a31e-b8aeda5670e7
                Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 04 January 2021
                : 08 March 2021
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: JP15KM0908001
                Funded by: doi http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP16H03287
                Funded by: doi http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP18K19154
                Funded by: doi http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP18K14347
                Funded by: doi http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP15H05843
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Cancer
                Chemistry
                Cancer
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