Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers
Targeted therapies for prostate, breast, and ovarian cancers are based on their activity against primary tumors rather than their anti‐metastatic activity. Consequently, there is an urgent need for new agents targeting the metastatic process. Emerging evidence correlates in vitro and in vivo cancer...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-11-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13513 |
| _version_ | 1797642594844409856 |
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| author | Amiram Sananes Itay Cohen Irit Allon Oshrit Ben‐David Raghda Abu Shareb Ksenia M. Yegodayev David Stepensky Moshe Elkabets Niv Papo |
| author_facet | Amiram Sananes Itay Cohen Irit Allon Oshrit Ben‐David Raghda Abu Shareb Ksenia M. Yegodayev David Stepensky Moshe Elkabets Niv Papo |
| author_sort | Amiram Sananes |
| collection | DOAJ |
| description | Targeted therapies for prostate, breast, and ovarian cancers are based on their activity against primary tumors rather than their anti‐metastatic activity. Consequently, there is an urgent need for new agents targeting the metastatic process. Emerging evidence correlates in vitro and in vivo cancer invasion and metastasis with increased activity of the proteases mesotrypsin (prostate and breast cancer) and kallikrein 6 (KLK6; ovarian cancer). Thus, mesotrypsin and KLK6 are attractive putative targets for therapeutic intervention. As potential therapeutics for advanced metastatic prostate, breast, and ovarian cancers, we report novel mesotrypsin‐ and KLK6‐based therapies, based on our previously developed mutants of the human amyloid β‐protein precursor Kunitz protease inhibitor domain (APPI). These mutants, designated APPI‐3M (prostate and breast cancer) and APPI‐4M (ovarian cancer), demonstrated significant accumulation in tumors and therapeutic efficacy in orthotopic preclinical models, with the advantages of long retention times in vivo, high affinity and favorable pharmacokinetic properties. The applicability of the APPIs, as a novel therapy and for imaging purposes, is supported by their good safety profile and their controlled and scalable manufacturability in bioreactors. |
| first_indexed | 2024-03-11T14:02:45Z |
| format | Article |
| id | doaj.art-a4cefe3f8f3c47aea4beb5cc1ffd954a |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-11T14:02:45Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-a4cefe3f8f3c47aea4beb5cc1ffd954a2023-11-02T04:03:00ZengWileyMolecular Oncology1574-78911878-02612023-11-0117112337235510.1002/1878-0261.13513Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancersAmiram Sananes0Itay Cohen1Irit Allon2Oshrit Ben‐David3Raghda Abu Shareb4Ksenia M. Yegodayev5David Stepensky6Moshe Elkabets7Niv Papo8Avram and Stella Goldstein‐Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelAvram and Stella Goldstein‐Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelInstitute of Pathology, Barzilai University Medical Center, Ashkelon, Israel ad Faculty of Health Sciences Ben‐Gurion University of the Negev Beer‐Sheva IsraelAvram and Stella Goldstein‐Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer‐Sheva IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer‐Sheva IsraelDepartment of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer‐Sheva IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer‐Sheva IsraelAvram and Stella Goldstein‐Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelTargeted therapies for prostate, breast, and ovarian cancers are based on their activity against primary tumors rather than their anti‐metastatic activity. Consequently, there is an urgent need for new agents targeting the metastatic process. Emerging evidence correlates in vitro and in vivo cancer invasion and metastasis with increased activity of the proteases mesotrypsin (prostate and breast cancer) and kallikrein 6 (KLK6; ovarian cancer). Thus, mesotrypsin and KLK6 are attractive putative targets for therapeutic intervention. As potential therapeutics for advanced metastatic prostate, breast, and ovarian cancers, we report novel mesotrypsin‐ and KLK6‐based therapies, based on our previously developed mutants of the human amyloid β‐protein precursor Kunitz protease inhibitor domain (APPI). These mutants, designated APPI‐3M (prostate and breast cancer) and APPI‐4M (ovarian cancer), demonstrated significant accumulation in tumors and therapeutic efficacy in orthotopic preclinical models, with the advantages of long retention times in vivo, high affinity and favorable pharmacokinetic properties. The applicability of the APPIs, as a novel therapy and for imaging purposes, is supported by their good safety profile and their controlled and scalable manufacturability in bioreactors.https://doi.org/10.1002/1878-0261.13513cancer imagingkallikreinsmetastasisprotease inhibitorsserine proteases |
| spellingShingle | Amiram Sananes Itay Cohen Irit Allon Oshrit Ben‐David Raghda Abu Shareb Ksenia M. Yegodayev David Stepensky Moshe Elkabets Niv Papo Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers Molecular Oncology cancer imaging kallikreins metastasis protease inhibitors serine proteases |
| title | Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers |
| title_full | Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers |
| title_fullStr | Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers |
| title_full_unstemmed | Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers |
| title_short | Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers |
| title_sort | serine protease inhibitors decrease metastasis in prostate breast and ovarian cancers |
| topic | cancer imaging kallikreins metastasis protease inhibitors serine proteases |
| url | https://doi.org/10.1002/1878-0261.13513 |
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