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Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma
Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085101/ https://www.ncbi.nlm.nih.gov/pubmed/27507190 http://dx.doi.org/10.18632/oncotarget.9552 |
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author | Carita, Guillaume Frisch-Dit-Leitz, Estelle Dahmani, Ahmed Raymondie, Chloé Cassoux, Nathalie Piperno-Neumann, Sophie Némati, Fariba Laurent, Cécile De Koning, Leanne Halilovic, Ensar Jeay, Sebastien Wylie, Andrew Emery, Caroline Roman-Roman, Sergio Schoumacher, Marie Decaudin, Didier |
author_facet | Carita, Guillaume Frisch-Dit-Leitz, Estelle Dahmani, Ahmed Raymondie, Chloé Cassoux, Nathalie Piperno-Neumann, Sophie Némati, Fariba Laurent, Cécile De Koning, Leanne Halilovic, Ensar Jeay, Sebastien Wylie, Andrew Emery, Caroline Roman-Roman, Sergio Schoumacher, Marie Decaudin, Didier |
author_sort | Carita, Guillaume |
collection | PubMed |
description | Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients. |
format | Online Article Text |
id | pubmed-5085101 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50851012016-10-31 Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma Carita, Guillaume Frisch-Dit-Leitz, Estelle Dahmani, Ahmed Raymondie, Chloé Cassoux, Nathalie Piperno-Neumann, Sophie Némati, Fariba Laurent, Cécile De Koning, Leanne Halilovic, Ensar Jeay, Sebastien Wylie, Andrew Emery, Caroline Roman-Roman, Sergio Schoumacher, Marie Decaudin, Didier Oncotarget Priority Research Paper Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients. Impact Journals LLC 2016-05-22 /pmc/articles/PMC5085101/ /pubmed/27507190 http://dx.doi.org/10.18632/oncotarget.9552 Text en Copyright: © 2016 Carita et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Carita, Guillaume Frisch-Dit-Leitz, Estelle Dahmani, Ahmed Raymondie, Chloé Cassoux, Nathalie Piperno-Neumann, Sophie Némati, Fariba Laurent, Cécile De Koning, Leanne Halilovic, Ensar Jeay, Sebastien Wylie, Andrew Emery, Caroline Roman-Roman, Sergio Schoumacher, Marie Decaudin, Didier Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma |
title | Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma |
title_full | Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma |
title_fullStr | Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma |
title_full_unstemmed | Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma |
title_short | Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma |
title_sort | dual inhibition of protein kinase c and p53-mdm2 or pkc and mtorc1 are novel efficient therapeutic approaches for uveal melanoma |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085101/ https://www.ncbi.nlm.nih.gov/pubmed/27507190 http://dx.doi.org/10.18632/oncotarget.9552 |
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