Melanoma
Posted May 7, 2021
J. William Harbour, M.D., Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center,
University of Miami Miller School of Medicine, Miami Florida, Fiscal Year 2014 (FY14) Idea Award with Special Focus
Uveal melanoma (UM) is a rare form of melanoma that develops from melanocytes in the eye (within the uvea which contains the iris, ciliary body, and choroid). The genetics and immune cell infiltration of UM is significantly different from cutaneous melanoma. As a result, the therapeutics approved to treat cutaneous melanoma, such as BRAF/MEK inhibitors and immunotherapy have not been successful in treating UM. Brachytherapy (radioactive seeds placed near the UM) is the main sight-saving treatment for primary UM, but 50% of patients still develop metastatic disease, most commonly to the liver. There is currently no treatment for metastatic UM.
Germline mutations in the BAP1 tumor suppressor are strongly associated with a predisposition to UM, as well as mesothelioma and renal cell carcinoma1. Additionally, these mutations are associated with metastatic risk and decreased survival. To date, there are no targeted therapeutics for BAP1. Dr. William Harbour was awarded a FY14 Idea Award with Special Focus to identify therapeutic molecules that inhibit BAP1-mutant cancers. In order to accomplish this, Dr. Harbour took a unique screening approach. Tumor suppressors are difficult to target directly with therapeutics, so one possibility is to target downstream effectors that are impacted by loss of BAP1 function.
BAP1 mutations cause striking developmental phenotypes in Xenopus laevis (African clawed frog) embryos that are easily observable2. Once a panel of drug candidates was identified following a high through-put screening of large drug compound libraries, they were subjected to the Xenopus embryo screen. Embryos lacking the BAP1 gene were treated with drug candidates. Successful drugs would be able to “rescue” the loss of BAP1 and restore normal embryonic development without any additional toxicity. Following this screen, one successful drug candidate, quisinostat, was identified. Quisinostat is a histone deacetylase (HDAC) inhibitor, which affects gene expression. The therapeutic efficacy of quisinostat in treating BAP1-mutant cancers was further validated using mouse xenograft models of uveal melanoma. Quisinostat was demonstrated to significantly reduce tumor growth in BAP-1 mutant uveal melanoma tumors, but not BAP-1 wildtype tumors. This work was recently published in the journal Molecular Cancer Research3.
This study highlights the importance of understanding the underlying genetic mechanisms of uveal melanoma and selecting therapeutics that specifically target those mutations. Dr. Harbour believes that inhibitors such as quisinostat could potentially be used to prevent the progression of uveal melanoma and other BAP1-mutant cancers. Further, their novel screening technique provides a framework for identifying additional therapeutics that target other tumor suppressors.
Publications:
1Carbone M, Harbour JW, Brugarolas J, Bononi A, Pagano I, Dey A, Krausz T, Pass HI, Yang H, Gaudino G. Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer. Cancer Discov. 2020 Aug;10(8):1103-1120. doi: 10.1158/2159-8290.CD-19-1220. Epub 2020 Jul 20. PMID: 32690542.
2Kuznetsov JN, Aguero TH, Owens DA, Kurtenbach S, Field MG, Durante MA, Rodriguez DA, King ML, Harbour JW. BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers. Sci Adv. 2019 Sep 18;5(9):eaax1738. doi: 10.1126/sciadv.aax1738. PMID: 31555735.
3Kuznetsoff JN, Owens DA, Lopez A, Rodriguez DA, Chee NT, Kurtenbach S, Bilbao D, Roberts ER, Volmar CH, Wahlestedt C, Brothers SP, and Harbour JW. 2020. Dual screen for efficacy and toxicity identifies HDAC inhibitor with distinctive activity spectrum for BAP1-mutant uveal melanoma. Mol Cancer Res. doi: 10.1158/1541-7786.MCR-20-0434. Epub ahead of print. PMID: 33077485.
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