The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers
Sortilin (SORT1) receptor-mediated endocytosis functions were exploited for this new approach for effective and safe treatments of gynecological cancers. Here, high expression of SORT1 was found in >75% of the clinically annotated ovarian and endometrial tumors analyzed by immunohistochemistry. T...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/8/1877 |
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| author | Jean-Christophe Currie Michel Demeule Cyndia Charfi Alain Zgheib Alain Larocque Bogdan Alexandru Danalache Amira Ouanouki Richard Béliveau Christian Marsolais Borhane Annabi |
| author_facet | Jean-Christophe Currie Michel Demeule Cyndia Charfi Alain Zgheib Alain Larocque Bogdan Alexandru Danalache Amira Ouanouki Richard Béliveau Christian Marsolais Borhane Annabi |
| author_sort | Jean-Christophe Currie |
| collection | DOAJ |
| description | Sortilin (SORT1) receptor-mediated endocytosis functions were exploited for this new approach for effective and safe treatments of gynecological cancers. Here, high expression of SORT1 was found in >75% of the clinically annotated ovarian and endometrial tumors analyzed by immunohistochemistry. Therefore, the anticancer properties of the peptide-drug conjugate TH1902, a peptide that targets SORT1 and which is linked to docetaxel molecules, were investigated both in vitro using ovarian and endometrial cancer cell cultures and in vivo using xenograft models. In vitro, TH1902 inhibited cell proliferation and triggered higher SORT1-dependent cell apoptosis than unconjugated docetaxel did in ES-2 and SKOV3 ovarian cancer cell lines. The uptake of the Alexa<sup>488</sup>-TH19P01 peptide from TH1902 was reduced upon siRNA-mediated silencing of SORT1. In vivo, weekly administration of TH1902 showed better tolerability compared to equivalent docetaxel doses and inhibited tumor growth in ovarian and endometrial xenograft mice models. TH1902 as a single agent inhibited ovarian tumor growth more than either of the unconjugated taxanes or carboplatin. Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin. |
| first_indexed | 2024-03-09T11:04:40Z |
| format | Article |
| id | doaj.art-ecd883d2b53a4caf83d666d76f039c6b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T11:04:40Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ecd883d2b53a4caf83d666d76f039c6b2023-12-01T01:04:35ZengMDPI AGCancers2072-66942022-04-01148187710.3390/cancers14081877The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial CancersJean-Christophe Currie0Michel Demeule1Cyndia Charfi2Alain Zgheib3Alain Larocque4Bogdan Alexandru Danalache5Amira Ouanouki6Richard Béliveau7Christian Marsolais8Borhane Annabi9Theratechnologies Inc., 2015 Peel Street, 11th Floor, Montréal, QC H3A 1T8, CanadaTheratechnologies Inc., 2015 Peel Street, 11th Floor, Montréal, QC H3A 1T8, CanadaTheratechnologies Inc., 2015 Peel Street, 11th Floor, Montréal, QC H3A 1T8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, CanadaTheratechnologies Inc., 2015 Peel Street, 11th Floor, Montréal, QC H3A 1T8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, CanadaTheratechnologies Inc., 2015 Peel Street, 11th Floor, Montréal, QC H3A 1T8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, CanadaSortilin (SORT1) receptor-mediated endocytosis functions were exploited for this new approach for effective and safe treatments of gynecological cancers. Here, high expression of SORT1 was found in >75% of the clinically annotated ovarian and endometrial tumors analyzed by immunohistochemistry. Therefore, the anticancer properties of the peptide-drug conjugate TH1902, a peptide that targets SORT1 and which is linked to docetaxel molecules, were investigated both in vitro using ovarian and endometrial cancer cell cultures and in vivo using xenograft models. In vitro, TH1902 inhibited cell proliferation and triggered higher SORT1-dependent cell apoptosis than unconjugated docetaxel did in ES-2 and SKOV3 ovarian cancer cell lines. The uptake of the Alexa<sup>488</sup>-TH19P01 peptide from TH1902 was reduced upon siRNA-mediated silencing of SORT1. In vivo, weekly administration of TH1902 showed better tolerability compared to equivalent docetaxel doses and inhibited tumor growth in ovarian and endometrial xenograft mice models. TH1902 as a single agent inhibited ovarian tumor growth more than either of the unconjugated taxanes or carboplatin. Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin.https://www.mdpi.com/2072-6694/14/8/1877gynecological cancerspeptide-drug conjugatesdocetaxelsortilin |
| spellingShingle | Jean-Christophe Currie Michel Demeule Cyndia Charfi Alain Zgheib Alain Larocque Bogdan Alexandru Danalache Amira Ouanouki Richard Béliveau Christian Marsolais Borhane Annabi The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers Cancers gynecological cancers peptide-drug conjugates docetaxel sortilin |
| title | The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers |
| title_full | The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers |
| title_fullStr | The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers |
| title_full_unstemmed | The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers |
| title_short | The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers |
| title_sort | peptide drug conjugate th1902 a new sortilin receptor mediated cancer therapeutic against ovarian and endometrial cancers |
| topic | gynecological cancers peptide-drug conjugates docetaxel sortilin |
| url | https://www.mdpi.com/2072-6694/14/8/1877 |
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