Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan
Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate...
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| Veröffentlicht in: | Scientific reports 2020-01, Vol.10 (1), p.973, Article 973 |
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| creator | Zeybek, Burak Manzano, Aranzazu Bianchi, Anna Bonazzoli, Elena Bellone, Stefania Buza, Natalia Hui, Pei Lopez, Salvatore Perrone, Emanuele Manara, Paola Zammataro, Luca Altwerger, Gary Han, Chanhee Tymon-Rosario, Joan Menderes, Gulden Ratner, Elena Silasi, Dan-Arin Huang, Gloria S. Azodi, Masoud Schwartz, Peter E. Santin, Alessandro |
| description | Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For
in vitro
experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test
in vivo
antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan
in vitro
, with IC
50
values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p |
| doi_str_mv | 10.1038/s41598-020-58009-3 |
| format | Article |
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in vitro
experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test
in vivo
antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan
in vitro
, with IC
50
values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-58009-3</identifier><identifier>PMID: 31969666</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/51 ; 692/4028 ; 692/420/755 ; Adenocarcinoma ; Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Adenosquamous ; Antibodies, Monoclonal, Humanized - pharmacology ; Antibodies, Monoclonal, Humanized - therapeutic use ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - metabolism ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Antitumor activity ; Camptothecin - analogs & derivatives ; Camptothecin - pharmacology ; Camptothecin - therapeutic use ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - metabolism ; Cell Adhesion Molecules - genetics ; Cell Adhesion Molecules - metabolism ; Cell Line, Tumor ; Cell surface ; Cell Survival - drug effects ; Cervical cancer ; Cervical carcinoma ; Cervix ; Female ; Flow cytometry ; Humanities and Social Sciences ; Humans ; Immunoconjugates - pharmacology ; Immunoconjugates - therapeutic use ; Immunohistochemistry ; Intravenous administration ; Irinotecan ; Metabolites ; Monoclonal antibodies ; multidisciplinary ; Placenta ; Polymerase chain reaction ; Science ; Science (multidisciplinary) ; Solid tumors ; Squamous cell carcinoma ; Surface markers ; Targeted cancer therapy ; Tumor cell lines ; Tumors ; Uterine Cervical Neoplasms - drug therapy ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - metabolism ; Xenografts</subject><ispartof>Scientific reports, 2020-01, Vol.10 (1), p.973, Article 973</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-c4b71d431236e0eead8427c2d61a6ede29495f53c2ac76a60be3badc396f73873</citedby><cites>FETCH-LOGICAL-c474t-c4b71d431236e0eead8427c2d61a6ede29495f53c2ac76a60be3badc396f73873</cites><orcidid>0000-0001-7705-3715 ; 0000-0003-2024-8102</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976591/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976591/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31969666$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zeybek, Burak</creatorcontrib><creatorcontrib>Manzano, Aranzazu</creatorcontrib><creatorcontrib>Bianchi, Anna</creatorcontrib><creatorcontrib>Bonazzoli, Elena</creatorcontrib><creatorcontrib>Bellone, Stefania</creatorcontrib><creatorcontrib>Buza, Natalia</creatorcontrib><creatorcontrib>Hui, Pei</creatorcontrib><creatorcontrib>Lopez, Salvatore</creatorcontrib><creatorcontrib>Perrone, Emanuele</creatorcontrib><creatorcontrib>Manara, Paola</creatorcontrib><creatorcontrib>Zammataro, Luca</creatorcontrib><creatorcontrib>Altwerger, Gary</creatorcontrib><creatorcontrib>Han, Chanhee</creatorcontrib><creatorcontrib>Tymon-Rosario, Joan</creatorcontrib><creatorcontrib>Menderes, Gulden</creatorcontrib><creatorcontrib>Ratner, Elena</creatorcontrib><creatorcontrib>Silasi, Dan-Arin</creatorcontrib><creatorcontrib>Huang, Gloria S.</creatorcontrib><creatorcontrib>Azodi, Masoud</creatorcontrib><creatorcontrib>Schwartz, Peter E.</creatorcontrib><creatorcontrib>Santin, Alessandro</creatorcontrib><title>Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For
in vitro
experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test
in vivo
antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan
in vitro
, with IC
50
values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.</description><subject>13/1</subject><subject>13/51</subject><subject>692/4028</subject><subject>692/420/755</subject><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenosquamous</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antitumor activity</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - pharmacology</subject><subject>Camptothecin - therapeutic use</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Cell Adhesion Molecules - genetics</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell surface</subject><subject>Cell Survival - drug effects</subject><subject>Cervical cancer</subject><subject>Cervical carcinoma</subject><subject>Cervix</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immunoconjugates - pharmacology</subject><subject>Immunoconjugates - therapeutic use</subject><subject>Immunohistochemistry</subject><subject>Intravenous administration</subject><subject>Irinotecan</subject><subject>Metabolites</subject><subject>Monoclonal antibodies</subject><subject>multidisciplinary</subject><subject>Placenta</subject><subject>Polymerase chain reaction</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Solid tumors</subject><subject>Squamous cell carcinoma</subject><subject>Surface markers</subject><subject>Targeted cancer therapy</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Uterine Cervical Neoplasms - drug therapy</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Xenografts</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9UcuO1DAQjBCIXS37AxyQJS5wMPiROPEFCY14SStxWc5Wx-kkHjL2YDsjhn_hX_Eyy7Jc6IPbUldXVauq6ilnrziT3etU80Z3lAlGm44xTeWD6lywuqFCCvHw3v-sukxpy0o1QtdcP67OJNdKK6XOq58bjAdnYSEWonU-7CCRPEMm4YARv-8jpkTmdQee5Bj2c-gXSJlYXBaa1jiCRbKD-BUjeXFdAFS8JBCRzG6alyNJ6JPL7oAkh8KLBHx2fRiOdIjrRGzw23WCjCSBdXn9UYR6MoWDy2jBP6kejbAkvLztF9WX9--uNx_p1ecPnzZvr6it2zqXt2_5UEsupEKGCENXi9aKQXFQOGA5WzdjI60A2ypQrEfZw2ClVmMru1ZeVG9OvPu13-Fg0ecIi9lHV047mgDO_DvxbjbFpVG6VY3mheD5LUEM31ZM2WzDGn3xbISsZd1pxm5kxAllY0gp4ninwJm5SdWcUjUlVfM7VSPL0rP73u5W_mRYAPIESGXkJ4x_tf9D-wuYDLKV</recordid><startdate>20200122</startdate><enddate>20200122</enddate><creator>Zeybek, Burak</creator><creator>Manzano, Aranzazu</creator><creator>Bianchi, 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carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan</title><author>Zeybek, Burak ; Manzano, Aranzazu ; Bianchi, Anna ; Bonazzoli, Elena ; Bellone, Stefania ; Buza, Natalia ; Hui, Pei ; Lopez, Salvatore ; Perrone, Emanuele ; Manara, Paola ; Zammataro, Luca ; Altwerger, Gary ; Han, Chanhee ; Tymon-Rosario, Joan ; Menderes, Gulden ; Ratner, Elena ; Silasi, Dan-Arin ; Huang, Gloria S. ; Azodi, Masoud ; Schwartz, Peter E. ; Santin, Alessandro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-c4b71d431236e0eead8427c2d61a6ede29495f53c2ac76a60be3badc396f73873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/1</topic><topic>13/51</topic><topic>692/4028</topic><topic>692/420/755</topic><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma 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Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zeybek, Burak</au><au>Manzano, Aranzazu</au><au>Bianchi, Anna</au><au>Bonazzoli, Elena</au><au>Bellone, Stefania</au><au>Buza, Natalia</au><au>Hui, Pei</au><au>Lopez, Salvatore</au><au>Perrone, Emanuele</au><au>Manara, Paola</au><au>Zammataro, Luca</au><au>Altwerger, Gary</au><au>Han, Chanhee</au><au>Tymon-Rosario, Joan</au><au>Menderes, Gulden</au><au>Ratner, Elena</au><au>Silasi, Dan-Arin</au><au>Huang, Gloria S.</au><au>Azodi, Masoud</au><au>Schwartz, Peter E.</au><au>Santin, Alessandro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-01-22</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>973</spage><pages>973-</pages><artnum>973</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For
in vitro
experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test
in vivo
antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan
in vitro
, with IC
50
values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31969666</pmid><doi>10.1038/s41598-020-58009-3</doi><orcidid>https://orcid.org/0000-0001-7705-3715</orcidid><orcidid>https://orcid.org/0000-0003-2024-8102</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2045-2322 |
| ispartof | Scientific reports, 2020-01, Vol.10 (1), p.973, Article 973 |
| issn | 2045-2322 2045-2322 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6976591 |
| source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry; Springer Nature OA Free Journals |
| subjects | 13/1 13/51 692/4028 692/420/755 Adenocarcinoma Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - metabolism Adenosquamous Antibodies, Monoclonal, Humanized - pharmacology Antibodies, Monoclonal, Humanized - therapeutic use Antigens, Neoplasm - genetics Antigens, Neoplasm - metabolism Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antitumor activity Camptothecin - analogs & derivatives Camptothecin - pharmacology Camptothecin - therapeutic use Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Cell Line, Tumor Cell surface Cell Survival - drug effects Cervical cancer Cervical carcinoma Cervix Female Flow cytometry Humanities and Social Sciences Humans Immunoconjugates - pharmacology Immunoconjugates - therapeutic use Immunohistochemistry Intravenous administration Irinotecan Metabolites Monoclonal antibodies multidisciplinary Placenta Polymerase chain reaction Science Science (multidisciplinary) Solid tumors Squamous cell carcinoma Surface markers Targeted cancer therapy Tumor cell lines Tumors Uterine Cervical Neoplasms - drug therapy Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Xenografts |
| title | Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T22%3A20%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cervical%20carcinomas%20that%20overexpress%20human%20trophoblast%20cell-surface%20marker%20(Trop-2)%20are%20highly%20sensitive%20to%20the%20antibody-drug%20conjugate%20sacituzumab%20govitecan&rft.jtitle=Scientific%20reports&rft.au=Zeybek,%20Burak&rft.date=2020-01-22&rft.volume=10&rft.issue=1&rft.spage=973&rft.pages=973-&rft.artnum=973&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-020-58009-3&rft_dat=%3Cproquest_pubme%3E2343489007%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2343489007&rft_id=info:pmid/31969666&rfr_iscdi=true |