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

恶性间皮瘤是一种侵袭性极强的疾病，发生在胸膜和腹膜的间皮衬里，最常见的原因是暴露于石棉(1，2)。此外，BAP1胚系突变导致BAP1肿瘤易感综合征(BAP1-TPDS)的个体，具有发展为包括间皮瘤在内的多种癌症的高风险。目前还没有治疗或预防这种致命疾病的选择，这种疾病的中位生存期为1年。 炎性介质是恶性间皮瘤发展的主要因素，并提示了癌症阻断的潜在靶点。间皮瘤的发展具有典型的潜伏期为几十年，这提供了一个时间框架，在此期间采取癌症预防策略，在肿瘤进展为恶性之前拦截正在发展的肿瘤。因此，任何用于预防恶性间皮瘤的药物都可能需要给药数十年。因此，理想的预防性药物不仅需要证明在预防间皮瘤方面的有效性，而且还必须表现出相对较高的安全性。 萝卜硫醚(SFN)是从花椰菜和其他十字花科蔬菜中提取的1-异硫氰酸-4-(甲基亚磺基)丁烷(3)，几十年来一直被研究用于癌症预防(4-13)SFN具有许多在高危患者人群中长期使用所需的特征，包括高生物利用度以及在体内具有良好的耐受性(8，9)。虽然SFN改变表观遗传机制的确切分子机制尚不清楚，但它们在修改/逆转组蛋白和DNA修饰、miRNA调节和信号通路方面发挥作用，这些信号通路涉及活性氧/氮物种、异种代谢酶、DNA损伤/修复、激酶、原癌基因、炎症、基质金属蛋白酶、上皮到间充质转化和免疫抑制[14]。 该项目的总体目标是1)确定在临床相关的人类剂量水平下口服萝卜硫素对恶性间皮瘤啮齿动物模型的化学预防效果，2)确定临床上相关的萝卜硫素疗效的药效学生物标记物，可以转化为人类临床试验，以及3)评估每天服用萝卜硫素的潜在长期毒性。 参考文献 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。腹膜间皮瘤的当前治疗方案和生物学：首届美国国立卫生研究院腹膜间皮瘤会议的会议纪要。安·昂科尔2006；17：1615-9。 2)Carbone M，Adusumilli PS，Alexander HR，Jr.，Baas P，Bardelli F，Bononi A，Bueno R，Felley-Bosco E，Galardo-Salle F，Jablons D，Mansfield As，Minaai M，de Perrot M，Pesvento P，Rusch V，Severson DT，Taoli E，Tsao A，Woodard G，Yang H，Zauderer MG，Pass HI。间皮瘤：预防、诊断和治疗的科学线索。《加州癌症杂志》2019；69：402-29。 3)Clarke JD，Dashwood RH，Ho E.萝卜硫素多靶点预防癌症。《癌症快报》2008；269：291-304。 4)格雷厄姆·S，戴亚尔·H，斯旺森·M，米特曼·A，威尔金森·G·饮食，结肠癌和直肠癌的流行病学。《癌症杂志》1978年；61：709-14。 5)Michaud DS，Spiegelman D，Clinton SK，RimType方程在这里。男性前瞻性队列中水果和蔬菜摄入量与膀胱癌发病率的关系。《癌症杂志》1999；91：605-13。 6)Myzak MC、Karplus PA、Chung FL、Dashwood RH。萝卜硫素的化学保护新机制：抑制组蛋白脱乙酰基酶。《癌症研究》2004；：5767-74。 7)Singh SV，Warin R，肖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。萝卜硫素通过增加自然杀伤细胞的细胞毒性来抑制流浪鼠前列腺癌的发生和肺转移。癌症研究2009；69：2117-25。 8)巴拉苏布拉曼虫S，Chew YC，Eckert RL.萝卜硫素通过依赖蛋白酶体的机制抑制皮肤癌细胞中多梳状蛋白的水平。Mol Pharmacol 2011；80：870-8。 9)Rajendran P，Delage B，Dashwood WM，Yu TW，Woth B，Williams DE，Ho E，Dashwood RH.在萝卜硫素处理的结肠癌细胞中组蛋白脱乙酰酶的转换和恢复：14-3-3和Pin1在HDAC3/SMRT辅阻遏子复合体解离/重组中的竞争作用。《摩尔癌症》2011；10：68。 10)Fisher ML，Ciavattone N，Grun D，Adhikary G，Eckert RL.萝卜硫素减少YAP/Np63α信号，从而减少癌症干细胞存活和肿瘤形成。2017年肿瘤目标；8：73407-18 11)Saha K，Fisher ML，Adhikary G，Grun D，Eckert RL.萝卜硫素在表皮鳞状细胞癌中抑制PRMT5/MEP50功能，从而减少肿瘤形成。致癌2017；38：827-36。 12)Yagishita Y，Faey JW，Dinkova-Kostova AT，Kensler TW.西兰花或萝卜硫素：重要的是来源还是剂量？分子2019；24：3593 13)柳中A、铃木H、武藤M、龟田T、Kakinoki N、吉田S、HiRose M、Ebihara T、Hyodo I.通过饮食摄入萝卜硫素来预防结肠癌。Funct Foods Health Dis 2019；9：392-411 14)Hudlikar R，王L，吴R，李S，Peter R，Shannar A，Chou PJ，刘x，刘Z，郭HD，Kongan表观遗传学/表观基因组学和异硫氰酸酯预防早期癌症。《癌症展望》2021；14：151--