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，在胸膜和腹膜的间皮层中发生，最常见的是由接触石棉引起的 (1, 2) 此外，具有 BAP1 种系突变的个体会导致 BAP1 肿瘤易感综合征。 (BAP1-TPDS)，具有患多种癌症的高风险，包括间皮瘤，目前没有针对这种致命疾病的治疗或预防选择。其中位生存期为 1 年。 炎症介质是恶性间皮瘤发展的主要因素，并且表明癌症间皮瘤的发展具有数十年的典型潜伏期，这为采取癌症预防策略以在肿瘤发展为恶性肿瘤之前拦截它们提供了时间框架。因此，任何用于预防恶性间皮瘤的药物都可能需要使用数十年，因此，理想的预防药物不仅需要证明其预防间皮瘤的功效，而且还必须能够发挥作用。还表现出相对较高的安全性。 萝卜硫素 (SFN) 是一种从西兰花和其他十字花科蔬菜中提取的 1-异硫氰酸基-4-(甲基亚磺酰基) 丁烷 (3)，几十年来一直在研究将其用作癌症预防剂 (4-13) SFN 具有许多特性需要在高风险患者群体中长期使用，包括高生物利用度以及体内耐受性良好 (8, 9)。 SFN 修饰的表观遗传机制尚不清楚，它们在修饰/逆转组蛋白和 DNA 修饰、miRNA 调节以及涉及活性氧/氮、异生物质代谢酶、DNA 损伤/修复、激酶、原癌基因的信号通路中发挥作用、炎症、基质金属蛋白酶、上皮间质转化和免疫抑制 (14)。 该项目的总体目标是 1) 确定口服萝卜硫素在临床相关人类剂量水平的恶性间皮瘤啮齿动物模型中的化学预防功效，2) 确定萝卜硫素功效的临床相关药效生物标志物，这些标志物可以转化为人体临床试验和 3) 评估每日服用萝卜硫素的潜在长期毒性。 参考 1) 哈桑·R、亚历山大·R、安特曼·K、博菲塔·P、Churg A、科伊特·D、豪斯纳·P、肯尼迪·R·金德勒·H、梅廷塔斯·M、穆蒂·L、昂达·M、帕斯·H、普雷姆库马尔·A、罗格利·V、斯特曼·D、舒格贝克P、Taub R、Verschraegen C. 腹膜间皮瘤的当前治疗选择和生物学：首届 NIH 腹膜会议总结间皮瘤会议。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、佩萨文托P, Rusch V, Severson DT, Taioli E, Tsao A, Woodard G, Yang H, Zauderer MG, 帕斯HI。间皮瘤：预防、诊断和治疗的科学线索。CA Cancer J Clin 2019；69:402-29。 3) Clarke JD、Dashwood RH、Ho E。萝卜硫素多靶点预防癌症。Cancer Lett 2008；269：291-304。 4) Graham S、Dayal H、Swanson M、Mittelman A、Wilkinson G。结肠癌和直肠癌流行病学中的饮食，1978 年国家癌症研究所杂志；61：709-14。 5) Michaud DS、Spiegelman D、Clinton SK、RimType 方程。m EB、Willett WC、Giovannucci EL。男性前瞻性队列中的水果和蔬菜摄入量与膀胱癌发病率。1999 年；91：605-13。 6) Myzak MC、Karplus PA、Chung FL、Dashwood RH。萝卜硫素化学保护的新机制：抑制组蛋白脱乙酰酶。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 萝卜硫素抑制前列腺。 TRAMP 小鼠的致癌和肺转移与自然杀伤细胞的细胞毒性增加有关。 2009；69：2117-25。 8) Balasubramanian S、Chew YC、Eckert RL。萝卜硫素通过蛋白酶体依赖性机制抑制皮肤癌细胞中的多梳蛋白水平。Mol Pharmacol 2011；80:870-8。 9) Rajendran P、Delage B、Dashwood WM、Yu TW、Wuth B、Williams DE、Ho E、Dashwood RH。萝卜硫素处理的结肠癌细胞中组蛋白脱乙酰酶周转和恢复：14-3-3 和 Pin1 的竞争作用HDAC3/SMRT 辅阻遏物复合物解离/重组。Mol Cancer 2011；10:68。 10) Fisher ML、Ciavattone N、Grun D、Adhikary G、Eckert RL。萝卜硫素减少 YAP/Np63alpha 信号传导以减少癌症干细胞存活和肿瘤形成。2017；8:73407-18。 11) Saha K、Fisher ML、Adhikary G、Grun D、Eckert RL。萝卜硫素抑制表皮鳞状细胞癌中的 PRMT5/MEP50 功能，从而减少肿瘤形成。2017；38：827-36。 12) Yagishita Y、Fahey JW、Dinkova-Kostova AT、Kensler TW。 西兰花或萝卜硫素：重要的是来源还是剂量？2019；24：3593 13) Yanaka A, Suzuki H, Mutoh M, Kamoshida T, Kakinoki N, Yoshida S, Hirose M, Ebihara T,Hyodo I. 通过膳食摄入萝卜硫素来化学预防结肠癌 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。表观遗传学/表观基因组学和异硫氰酸盐预防早期癌症。 2021；14：151-64