PREVENT Preclinical Drug Development Program: Preclinical Efficacy and Intermediate BiomarkersTask Order Title: Sulforaphane for the Prevention of Malignant Mesothelioma

PREVENT 临床前药物开发计划：临床前功效和中间生物标志物任务单标题：萝卜硫素用于预防恶性间皮瘤

• 批准号: 10836806
• 负责人: JOSEPH TESTA
• 金额: $ 119.93万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2026-05-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836806
• 关键词: Asbestos; Asbestos-Related Malignant Mesothelioma; Biological Availability; Biology; Blood; Broccoli - dietary; Butane; Characteristics; Chemoprevention; Chemopreventive Agent; Clinical Trials; Colon Carcinoma; Complex; DNA Damage; DNA Modification Process; Development; Diagnosis; Diet; Dietary intake; Disease; Dissociation; Dose; Enzymes; Epigenetic Process; Equation; Exposure to; Germ-Line Mutation; Goals; HDAC3 gene; Health Food; Histone Deacetylase; Histone Deacetylase Inhibitor; Histopathology; Human; Immunosuppression; Incidence; Individual; Inflammation; Inflammation Mediators; Intake; Intercept; Isothiocyanates; Malignant Neoplasms; Malignant mesothelioma; Malignant neoplasm of urinary bladder; Measurement; Mesothelioma; Mesothelium; Metalloproteins; Metastatic Neoplasm to the Lung; MicroRNAs; Molecular; Natural Killer Cell toxicity; Natural Killer Cells; Nitrogen; Oral Administration; Organ; Oxygen; Pathology; Peritoneal Mesothelioma; Peritoneum; Phosphotransferases; Pleura; Polycomb; Preclinical Drug Development; Predisposition; Prevention; Prevention strategy; Preventive; Program Development; Prospective cohort; Proteins; Proto-Oncogenes; Recovery; Rectal Cancer; Regulation; Rodent Model; Safety; Signal Pathway; Signal Transduction; Skin Cancer; Squamous cell carcinoma; Sulforaphane; Syndrome; Therapeutic; Time; Tissues; Toxic effect; Translating; United States National Institutes of Health; Xenobiotics; cancer cell; cancer epidemiology; cancer prevention; cancer stem cell; carcinogenesis; clinically relevant; cruciferous vegetable; epigenomics; epithelial to mesenchymal transition; fruits and vegetables; genetic corepressor; high risk; histone modification; in vivo; male; meetings; multicatalytic endopeptidase complex; novel; patient population; pharmacodynamic biomarker; preclinical efficacy; prevent; prostate carcinogenesis; repaired; stem cell survival; symposium; tissue biomarkers; transgenic adenocarcinoma of mouse prostate; tumor

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. Ann Oncol 2006;17:1615-9. 2) Carbone M, Adusumilli PS, Alexander HR, Jr., Baas P, Bardelli F, Bononi A, Bueno R, Felley- Bosco E, Galateau-Salle F, Jablons D, Mansfield AS, Minaai M, de Perrot M, Pesavento P, Rusch V, Severson DT, Taioli E, Tsao A, Woodard G, Yang H, Zauderer MG, Pass HI. Mesothelioma: scientific clues for prevention, diagnosis, and therapy. CA Cancer J Clin 2019;69:402-29. 3) Clarke JD, Dashwood RH, Ho E. Multi-targeted prevention of cancer by sulforaphane. Cancer Lett 2008;269:291-304. 4) Graham S, Dayal H, Swanson M, Mittelman A, Wilkinson G. Diet in the epidemiology of cancer of the colon and rectum. J Natl Cancer Inst 1978;61:709-14. 5) Michaud DS, Spiegelman D, Clinton SK, RimType equation here.m EB, Willett WC, Giovannucci EL. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl CancerInst 1999;91:605-13. 6) Myzak MC, Karplus PA, Chung FL, Dashwood RH. 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

恶性间皮瘤是一种极具侵袭性的疾病，发生在胸膜和腹膜的间皮层，最常见的原因是暴露于石棉（1,2）。此外，携带BAP1种系突变导致BAP1肿瘤易感综合征（BAP1- tpds）的个体，患包括间皮瘤在内的几种癌症的风险很高。这种致命疾病的中位生存期为1年，目前尚无治疗或预防方案。