Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma.

Autor:	Kuznetsoff JN; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida., Owens DA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida., Lopez A; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida., Rodriguez DA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida., Chee NT; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida., Kurtenbach S; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida., Bilbao D; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida., Roberts ER; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida., Volmar CH; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida., Wahlestedt C; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida., Brothers SP; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida., Harbour JW; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. harbour@miami.edu.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2021 Feb; Vol. 19 (2), pp. 215-222. Date of Electronic Publication: 2020 Oct 19.
DOI:	10.1158/1541-7786.MCR-20-0434
Abstrakt:	Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor-suppressor genes. BAP1 is one such tumor suppressor that is frequently inactivated in a variety of cancers, including uveal melanoma, renal cell carcinoma, and mesothelioma. Because BAP1 is an epigenetic transcriptional regulator of developmental genes, we designed a two-phase drug screen involving a cell-based rescue screen of transcriptional repression caused by BAP1 loss, followed by an in vivo screen of lead compounds for rescue of a BAP1-deficient phenotype with minimal toxicity in Xenopus embryos. The first screen identified 9 compounds, 8 of which were HDAC inhibitors. The second screen eliminated all except one compound due to inefficacy or toxicity. The resulting lead compound, quisinostat, has a distinctive activity spectrum, including high potency against HDAC4, which was recently shown to be a key target of BAP1. Quisinostat was further validated in a mouse model and found to prevent the growth of BAP1-mutant uveal melanomas. This innovative strategy demonstrates the potential for identifying therapeutic compounds that target tumor-suppressor mutations in cancer. IMPLICATIONS: Few drugs have been identified that target mutations in tumor suppressors. Using a novel 2-step screening approach, strategy, we identified quisinostat as a candidate for therapy in BAP1-mutant uveal melanoma. HDAC4 is implicated as a key target in uveal melanoma and perhaps other BAP1-mutant cancers. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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