Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis
Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/10/971 |
| _version_ | 1797513478819282944 |
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| author | Natalie Koons Nicole Amato Scott Sauer David Warshawsky Dalit Barkan Chand Khanna |
| author_facet | Natalie Koons Nicole Amato Scott Sauer David Warshawsky Dalit Barkan Chand Khanna |
| author_sort | Natalie Koons |
| collection | DOAJ |
| description | Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs. |
| first_indexed | 2024-03-10T06:17:09Z |
| format | Article |
| id | doaj.art-5ab316e93ced435f8efe43144842109e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T06:17:09Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-5ab316e93ced435f8efe43144842109e2023-11-22T19:35:19ZengMDPI AGPharmaceuticals1424-82472021-09-01141097110.3390/ph14100971Assessing a Novel 3D Assay System for Drug Screening against OS MetastasisNatalie Koons0Nicole Amato1Scott Sauer2David Warshawsky3Dalit Barkan4Chand Khanna5Surgery Department, Massachusetts Veterinary Referral Hospital, Woburn, MA 01801, USASurgery Department, Massachusetts Veterinary Referral Hospital, Woburn, MA 01801, USAVuja De Sciences, Inc., Natick, MA 01760, USAVuja De Sciences, Inc., Natick, MA 01760, USADepartment of Human Biology and Medical Sciences, University of Haifa, Haifa 3498838, IsraelEthos Discovery, Woburn, MA 01801, USAOsteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.https://www.mdpi.com/1424-8247/14/10/971osteosarcomametastatic endurancesmall molecule inhibitorsoclacitinibregorafenibsaracatinib |
| spellingShingle | Natalie Koons Nicole Amato Scott Sauer David Warshawsky Dalit Barkan Chand Khanna Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis Pharmaceuticals osteosarcoma metastatic endurance small molecule inhibitors oclacitinib regorafenib saracatinib |
| title | Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis |
| title_full | Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis |
| title_fullStr | Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis |
| title_full_unstemmed | Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis |
| title_short | Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis |
| title_sort | assessing a novel 3d assay system for drug screening against os metastasis |
| topic | osteosarcoma metastatic endurance small molecule inhibitors oclacitinib regorafenib saracatinib |
| url | https://www.mdpi.com/1424-8247/14/10/971 |
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