Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives
Among Uveal Melanoma (UM) driver mutations, those involving <i>GNAQ</i> or <i>GNA11</i> genes are the most frequent, while a minor fraction of tumors bears mutations in the <i>PLCB4</i> or <i>CYSLTR2</i> genes. Direct inhibition of constitutively activ...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-06-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/6/846 |
| _version_ | 1797710940676816896 |
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| author | Michela Croce Silvano Ferrini Ulrich Pfeffer Rosaria Gangemi |
| author_facet | Michela Croce Silvano Ferrini Ulrich Pfeffer Rosaria Gangemi |
| author_sort | Michela Croce |
| collection | DOAJ |
| description | Among Uveal Melanoma (UM) driver mutations, those involving <i>GNAQ</i> or <i>GNA11</i> genes are the most frequent, while a minor fraction of tumors bears mutations in the <i>PLCB4</i> or <i>CYSLTR2</i> genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas <i>BRAFV600E</i>-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, <i>BAP1</i> loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy. |
| first_indexed | 2024-03-12T06:59:36Z |
| format | Article |
| id | doaj.art-fe4c0927a4544f86a9a3ac2da2eed12a |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:59:36Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fe4c0927a4544f86a9a3ac2da2eed12a2023-09-02T23:51:25ZengMDPI AGCancers2072-66942019-06-0111684610.3390/cancers11060846cancers11060846Targeted Therapy of Uveal Melanoma: Recent Failures and New PerspectivesMichela Croce0Silvano Ferrini1Ulrich Pfeffer2Rosaria Gangemi3IRCCS Ospedale Policlinico San Martino, 16132 Genoa, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genoa, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genoa, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genoa, ItalyAmong Uveal Melanoma (UM) driver mutations, those involving <i>GNAQ</i> or <i>GNA11</i> genes are the most frequent, while a minor fraction of tumors bears mutations in the <i>PLCB4</i> or <i>CYSLTR2</i> genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas <i>BRAFV600E</i>-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, <i>BAP1</i> loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy.https://www.mdpi.com/2072-6694/11/6/846uveal melanomadriver mutationssignaling pathwaystargeted therapies |
| spellingShingle | Michela Croce Silvano Ferrini Ulrich Pfeffer Rosaria Gangemi Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives Cancers uveal melanoma driver mutations signaling pathways targeted therapies |
| title | Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives |
| title_full | Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives |
| title_fullStr | Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives |
| title_full_unstemmed | Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives |
| title_short | Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives |
| title_sort | targeted therapy of uveal melanoma recent failures and new perspectives |
| topic | uveal melanoma driver mutations signaling pathways targeted therapies |
| url | https://www.mdpi.com/2072-6694/11/6/846 |
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