Malignant mesothelioma is an extremely aggressive disease that develops in the mesothelial lining of the pleura and peritoneum and is most commonly caused by exposure to asbestos (1, 2). In addition, individuals with a germline mutation of BAP1, leading to BAP1 tumor predisposition syndrome (BAP1-TPDS), carry a high risk of developing several cancers, including mesothelioma. There are currently no therapeutic or preventive options for this deadly disease, which has a median survival of 1 year. Inflammatory mediators are major contributors to the development of malignant mesothelioma and suggest potential targets for cancer interception. Mesothelioma develops with a typical latency period of several decades, providing a time frame in which to pursue cancer preventive strategies to intercept developing tumors before they progress to malignancy. Any agent used to prevent malignant mesothelioma would thus potentially need to be administered for decades. Therefore, the ideal preventive agent not only needs to demonstrate efficacy in preventing mesothelioma, but must also demonstrate a relatively high safety profile. Sulforaphane (SFN), 1-isothiocyanato-4-(methylsulfinyl) butane derived from broccoli and other cruciferous vegetables (3), has been studied for use as a cancer preventive agent for several decades (4-13) SFN possess many of the characteristics required for long term use in a high-risk patient population, including high bioavailability as well as being well-tolerated in vivo (8, 9). While the precise molecular mechanisms by which SFN modifies the epigenetic machinery are unclear, they play a role in modifying/reversing histone and DNA modifications, miRNA regulation, and signaling pathways that involve reactive oxygen/nitrogen species, xenobiotic metabolizing enzymes, DNA damage/repair, kinases, proto-oncogenes, inflammation, matrix metalloprotein¬ases, epithelial-to-mesenchymal transition, and immune suppression (14). The overall goal of this project is to 1) determine the chemopreventive efficacy of orally administered sulforaphane in a rodent model of malignant mesothelioma at clinically relevant human dose levels, 2) identify clinically relevant pharmacodynamic biomarkers of sulforaphane efficacy that could be translated to human clinical trials, and 3) assess the potential long-term toxicity of daily sulforaphane administration. References 1) Hassan R, Alexander R, Antman K, Boffetta P, Churg A, Coit D, Hausner P, Kennedy R Kindler H, Metintas M, Mutti L, Onda M, Pass H, Premkumar A, Roggli V, Sterman D, Sugarbaker P, Taub R, Verschraegen C. Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference. 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A novel mechanism of chemoprotectionby sulforaphane: inhibition of histone deacetylase. Cancer Res 2004;64:5767-74. 7) Singh SV, Warin R, Xiao D, Powolny AA, Stan SD, Arlotti JA, Zeng Y, Hahm ER, Marynowski SW, Bommareddy A, Desai D, Amin S, Parise RA, Beumer JH, Chambers WH. Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells. Cancer Res 2009;69:2117-25. 8) Balasubramanian S, Chew YC, Eckert RL. Sulforaphane suppresses polycomb group protein level via a proteasome-dependent mechanism in skin cancer cells. Mol Pharmacol 2011;80:870-8. 9) Rajendran P, Delage B, Dashwood WM, Yu TW, Wuth B, Williams DE, Ho E, Dashwood RH.Histone deacetylase turnover and recovery in sulforaphane-treated colon cancer cells: competing actions of 14-3-3 and Pin1 in HDAC3/SMRT corepressor complex dissociation/reassembly. Mol Cancer 2011;10:68. 10) Fisher ML, Ciavattone N, Grun D, Adhikary G, Eckert RL. Sulforaphane reduces YAP/Np63alpha signaling to reduce cancer stem cell survival and tumor formation. Oncotarget 2017;8:73407-18 11) Saha K, Fisher ML, Adhikary G, Grun D, Eckert RL. Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumorformation. Carcinogenesis 2017;38:827-36. 12) Yagishita Y, Fahey JW, Dinkova-Kostova AT, Kensler TW. Broccoli or sulforaphane: is it thesource or dose that matters? Molecules 2019;24:3593 13) Yanaka A, Suzuki H, Mutoh M, Kamoshida T, Kakinoki N, Yoshida S, Hirose M, Ebihara T,Hyodo I. Chemoprevention against colon cancer by dietary intake of sulforaphane. Funct Foods Health Dis 2019;9:392-411 14) Hudlikar R, Wang L, Wu R, Li S, Peter R, Shannar A, Chou PJ, Liu X, Liu Z, Kuo HD, KongAN. Epigenetics/epigenomics and prevention of early stages of cancer by isothiocyanates. Cancer Prev Res 2021;14:151-64