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; 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为侵略性的疾病，它在胸膜和腹膜的间皮壁中发展，最常见的是暴露于石棉上（1、2）。此外，患有BAP1系生殖线突变的个体，导致BAP1肿瘤易感综合征（BA​​P1-TPDS），具有患几种癌症（包括间皮瘤）的高风险。目前没有这种致命疾病的治疗或预防选择，该疾病的中位生存期为1年。 炎症性介体是导致恶性间皮瘤发展的主要因素，并提出了潜在的癌症截骨靶标。间皮瘤的发展为几十年的典型潜伏期，为购买癌症预防策略的时间范围提供了拦截肿瘤在恶性肿瘤发展之前拦截肿瘤的时间范围。因此，几十年来可能需要使用用于预防恶性间皮瘤的任何药物。因此，理想的预防剂不仅需要在预防间皮瘤方面表现出效率，而且还必须表现出相对较高的安全性。 磺胺硫烷（SFN），1-异硫氰酸4-（甲基磺胺基）丁烷衍生自Broccoli和其他十字花科蔬菜（3）（3），已研究数十年来用作癌症预防剂（4-13）SFN在包括高级患者（包括较高的比较）中，包括多个较高的sfn潜在特征，包括众多的比率，包括众多的Bio-Rio-Rio-Rio-Rio cover viv a，包括高级企业，包括viv sfive viv。 （8，9）。 SFN修改表观遗传机器的精确分子机制尚不清楚，但它们在修饰/逆转组蛋白和DNA修饰，miRNA调节以及涉及反应性氧/氮/硝基含氧于反应性氧/硝基含量的enzys，dNA损伤/修复酶，kito，kito assos，kincos，kincos，Kincos，kincos，Kincos，Kincos，Kincos，Kincos，Kincos，Kincos，Kincos，Kincos，Kincos，蛋白质和信号通路方面发挥作用。金属蛋白酶，上皮到间质转变和免疫抑制（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的恶性间皮瘤的啮齿动物模型中，口服硫二烷的化学预防效果，2）确定可以将硫酸硫烷有效性的药物生物标记物识别为可将硫酸硫烷有效性转化为人类临床试验的长期持续性疗法，并评估3）潜在的效率。 参考 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首次NIH腹膜间皮瘤会议。 Ann Oncol 2006; 17：1615-9。 2）Carbone M，Adumilli PS，Alexander Hr， Zauderer MG，通过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，HoE。Sulforaphane对癌症的多目标预防。癌症Lett 2008; 269：291-304。 4）Graham S，Dayal H，Swanson M，Mittelman A，Wilkinson G.结肠和直肠癌流行病学中的饮食。 J Natl Cancer Inst 1978; 61：709-14。 5）Michaud DS，Spiegelman D，Clinton SK，Rimtype方程。MEB，Willett WC，Giovannucci El。男性前瞻性队列中膀胱癌的果实和蔬菜摄入量和发病率。 J Natl Cancerinst 1999; 91：605-13。 6）Myzak MC，Karplus PA，Chung FL，Dashwood RH。化学保护的新型机制：抑制组蛋白脱乙酰基酶。 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，Bommarddy A，Bommarddy A，Desai D，Amin S，Parise RA，Beumer RA，Beumer JH，Chambers WH。硫烷抑制前列腺癌发生和肺动物中的肺转移，与天然杀伤细胞的细胞毒性增加有关。 Cancer Res 2009; 69：2117-25。 8）Balasubramanian S，Chew YC，Eckert RL。 Sulforaphane通过皮肤癌细胞中的蛋白酶体依赖机制抑制Polycomb组蛋白水平。 Mol Pharmacol 2011; 80：870-8。 9）Rajendran P，Derage B，Dashwood WM，Yu TW，Wuth B，Williams de，Ho E，Dashwood RH。组蛋白脱乙酰基酶的周转率和经硫烷治疗的结肠癌细胞的恢复：HDAC3/SMRT Corepressor复合物分解/重组中的14-3-3和PIN1的竞争作用。 Mol Cancer 2011; 10：68。 10）Fisher ML，Ciavattone N，Grun D，Adhikary G，Eckert RL。 Sulforaphane降低了YAP/NP63Alpha信号传导，以减少癌细胞存活和肿瘤的形成。 Oncotarget 2017; 8：73407-18 11）Saha K，Fisher ML，Adhikary G，Grun D，Eckert RL。 Sulforaphane抑制表皮鳞状细胞癌中的PRMT5/MEP50功能，从而降低肿瘤。癌变2017; 38：827-36。 12）Yagishita Y，Fahey JW，Dinkova-Kostova，Kensler TW。西兰花或硫芬：重要的是至关重要吗？分子2019; 24：3593 13）Yanaka A，Suzuki H，Mutoh M，Kamoshida T，Kakinoki N，Yoshida S，Hirose M，Hirose M，Ebihara T，HyodoI。通过甲氟芬饮食摄入的饮食摄入，对结肠癌的化学预防。 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。异硫氰酸盐的表观遗传学/表观基因组学和预防癌症的早期阶段。 Cancer Prev Res 2021; 14：151-64