A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma
Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies sh...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-05-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-021-00505-0 |
| _version_ | 1818600954647281664 |
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| author | Surein Arulananda Megan O’Brien Marco Evangelista Laura J. Jenkins Ashleigh R. Poh Marzena Walkiewicz Trishe Leong John M. Mariadason Jonathan Cebon Srividya B. Balachander Justin R. Cidado Erinna F. Lee Thomas John Walter D. Fairlie |
| author_facet | Surein Arulananda Megan O’Brien Marco Evangelista Laura J. Jenkins Ashleigh R. Poh Marzena Walkiewicz Trishe Leong John M. Mariadason Jonathan Cebon Srividya B. Balachander Justin R. Cidado Erinna F. Lee Thomas John Walter D. Fairlie |
| author_sort | Surein Arulananda |
| collection | DOAJ |
| description | Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL. |
| first_indexed | 2024-12-16T12:43:42Z |
| format | Article |
| id | doaj.art-ad883c64d8a746e29bfa7c2330196e64 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-12-16T12:43:42Z |
| publishDate | 2021-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-ad883c64d8a746e29bfa7c2330196e642022-12-21T22:31:21ZengNature Publishing GroupCell Death Discovery2058-77162021-05-01711910.1038/s41420-021-00505-0A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesotheliomaSurein Arulananda0Megan O’Brien1Marco Evangelista2Laura J. Jenkins3Ashleigh R. Poh4Marzena Walkiewicz5Trishe Leong6John M. Mariadason7Jonathan Cebon8Srividya B. Balachander9Justin R. Cidado10Erinna F. Lee11Thomas John12Walter D. Fairlie13Olivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteDepartment of Clinical Pathology, University of MelbourneOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteBioscience, Oncology R&D, AstraZenecaBioscience, Oncology R&D, AstraZenecaOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteOlivia Newton-John Cancer Research InstituteAbstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.https://doi.org/10.1038/s41420-021-00505-0 |
| spellingShingle | Surein Arulananda Megan O’Brien Marco Evangelista Laura J. Jenkins Ashleigh R. Poh Marzena Walkiewicz Trishe Leong John M. Mariadason Jonathan Cebon Srividya B. Balachander Justin R. Cidado Erinna F. Lee Thomas John Walter D. Fairlie A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma Cell Death Discovery |
| title | A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma |
| title_full | A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma |
| title_fullStr | A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma |
| title_full_unstemmed | A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma |
| title_short | A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma |
| title_sort | novel bh3 mimetic azd0466 targeting bcl xl and bcl 2 is effective in pre clinical models of malignant pleural mesothelioma |
| url | https://doi.org/10.1038/s41420-021-00505-0 |
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