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Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant
Jeffim N Kuznetsoff1,2,3, Dawn A Owens1,2,3, Andy Lopez1,2,3
1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.
Abstract:
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.
Insights
Researchers identified quisinostat, a potent HDAC inhibitor, as a promising therapy for BAP1-mutant cancers like uveal melanoma. This novel drug screen targets tumor suppressor gene mutations, offering new hope for cancer treatment.
Area of Science:
- Oncology
- Cancer Therapeutics
- Epigenetics
Background:
- Targeted cancer therapies often focus on oncogenes, with limited success against tumor suppressor gene mutations.
- BRCA1-associated protein 1 (BAP1) is a tumor suppressor frequently inactivated in cancers such as uveal melanoma, renal cell carcinoma, and mesothelioma.
- BAP1 functions as an epigenetic transcriptional regulator crucial for developmental genes.
Purpose of the Study:
- To develop and implement a novel two-phase drug screening strategy to identify therapeutic compounds targeting BAP1-mutant cancers.
- To discover compounds that can rescue transcriptional repression caused by BAP1 loss and validate their efficacy and safety in vivo.
- To identify potential therapeutic agents for cancers with inactivating mutations in tumor suppressor genes.
Main Methods:
- A two-phase drug screen was employed: a cell-based rescue screen for transcriptional repression and an in vivo screen in Xenopus embryos.
- The first phase identified 9 potential compounds, predominantly histone deacetylase (HDAC) inhibitors.
- The second phase evaluated lead compounds for efficacy and toxicity in a BAP1-deficient Xenopus model.
Main Results:
- The screening identified quisinostat as the sole effective compound with minimal toxicity.
- Quisinostat demonstrated high potency against HDAC4, a known key target of BAP1.
- Validation in a mouse model confirmed quisinostat's ability to inhibit the growth of BAP1-mutant uveal melanomas.
Conclusions:
- This study presents an innovative strategy for discovering targeted therapies against tumor suppressor mutations.
- Quisinostat is identified as a promising candidate for treating BAP1-mutant uveal melanoma and potentially other BAP1-mutant cancers.
- HDAC4 is implicated as a critical therapeutic target in uveal melanoma and other BAP1-mutant malignancies.
