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New targeted and epigenetic therapeutic strategies for the treatment of uveal melanoma

Abstract

Uveal melanoma (UM) is a rare, genetically bland ocular malignancy with excellent local treatment options, but no disease-specific therapies are approved for use in the metastatic setting by the Food and Drug Administration. Metastatic UM (mUM) confers a prognosis of ~15 months. Unlike cutaneous melanoma, UM is poorly responsive to checkpoint inhibitors and cytotoxic chemotherapy highlighting the importance of clarifying vulnerable disease-specific mechanisms, such as cell cycle or metabolic pathways necessary for tumor growth and survival. The elucidation of signaling pathways downstream of the frequently mutated GNA GTPase such as PKC/MAPK/ERK/MEK, PI3K/AKT, and YAP-Hippo have offered potential targets. Potentially druggable epigenetic targets due to BAP1-mutated UM have also been identified, including proteins involved with histone deacetylation and DNA splicing. This review describes the preclinical rationale for the development of targeted therapies and current strategies currently being studied in clinical trials or will be in the near future.

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Fig. 1: The Gα signaling pathway in uveal melanoma.
Fig. 2: Targetable epigenetic drivers of uveal melanoma.

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AZW and ABM were responsible for designing the review, writing the report, screening potentially eligible studies, extracting and analysing data, interpreting results, updating reference lists, and creating tables. RDC was responsible for designing the review, writing the report, screening potentially eligible studies, extracting and analysing data, interpreting results, creating tables, and providing feedback on the report.

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Correspondence to Richard D. Carvajal.

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RDC serves as a consultant and/or advisory board member for AstraZeneca, Aura Biosciences, Iconic Therapeutics, Janssen, Merck, Novartis, Rgenix, and Thomson Reuter. The remaining authors declare no competing interests.

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Wei, A.Z., Maniar, A.B. & Carvajal, R.D. New targeted and epigenetic therapeutic strategies for the treatment of uveal melanoma. Cancer Gene Ther 29, 1819–1826 (2022). https://doi.org/10.1038/s41417-022-00443-8

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