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略性的疾病，在胸膜和腹膜的间皮瘤衬里发展，最常见的是由于暴露于石棉（1，2）。此外，具有BAP 1种系突变的个体，导致BAP 1肿瘤易感综合征（BAP 1-TPDS），具有发展多种癌症的高风险，包括间皮瘤。目前没有治疗或预防这种致命疾病的选择，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，并提示癌症拦截的潜在靶点。间皮瘤的发展具有典型的几十年的潜伏期，提供了一个时间框架，在此期间采取癌症预防策略，以在肿瘤进展为恶性肿瘤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服用数十年。因此，理想的预防剂不仅需要证明在预防间皮瘤方面的有效性，而且还必须证明相对高的安全性。 萝卜硫素（SFN），1-异硫氰酸基-4-（甲基亚磺酰基）丁烷，来源于花椰菜和其他十字花科蔬菜（3），已被研究用作癌症预防剂几十年（4-13）SFN具有许多高风险患者群体长期使用所需的特征，包括高生物利用度以及体内耐受性良好（8，9）。虽然SFN修饰表观遗传机制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调节和涉及活性氧/氮物质、异生物质代谢酶、DNA损伤/修复、激酶、原癌基因、炎症、基质金属蛋白酶、上皮-间充质转化和免疫抑制的信号传导途径中发挥作用（14）。 该项目的总体目标是：1）确定在临床相关人类剂量水平下，在恶性间皮瘤啮齿动物模型中口服给予莱菔硫烷的化学预防功效，2）确定可转化为人类临床试验的莱菔硫烷功效的临床相关药效学生物标志物，以及3）评估每日给予莱菔硫烷的潜在长期毒性。 引用 1)哈桑R，亚历山亚历山大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.当前腹膜间皮瘤的治疗选择和生物学：第一届NIH腹膜间皮瘤会议摘要。Ann Oncol 2006;17：1615-9. 2)Carbone M，Adusumilli PS，亚历山大HR，Jr.，Baas P，Bardelli F，Bononi A，Brono R，Felley- Bosco E，Galateau-Salle F，Jablons D，曼斯菲尔德AS，Minaai M，de Perrot M，Pesavento P，Rusch V，Severson DT，Taioli 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。CA Cancer J Clin 2019;69：402-29. 3)Clarke JD，Dashwood RH，Ho E.萝卜硫素对癌症的多靶向预防。癌症通讯2008;269：291-304. 4)[10] Graham S，Dayal H，Swanson M，Mittelman A，威尔金森G.饮食在结肠癌和直肠癌的流行病学。J Natl Cancer Inst 1978;61：709-14. 5)Michaud DS，Spiegelman D，Clinton SK，RimType equation here.m EB，Willett WC，Giovannucci EL.男性前瞻性队列中水果和蔬菜摄入与膀胱癌发病率的关系J Natl CancerInst 1999;91：605-13. 6)Myzak MC，Karplus PA，Chung FL，Dashwood RH.萝卜硫素化学保护作用的新机制：抑制组蛋白去乙酰化酶。癌症研究2004;64：5767-74。 7)Singh SV，瓦林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.莱菔硫烷抑制TRAMP小鼠中的前列腺癌发生和肺转移，与自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.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组蛋白水平。分子药理学2011;80：870-8。 9)Rajendran P，Delage B，Dashwood WM，Yu TW，Wuth B，威廉姆斯DE，Ho E，Dashwood RH.组蛋白去乙酰化酶周转和萝卜硫素处理的结肠癌细胞的恢复：HDAC 3/SMRT辅阻遏物复合物解离/重组中14-3-3和Pin 1的竞争作用。Mol Cancer 2011;10：68. 10)Fisher ML，Ciavattone N，Grun D，Adhikary G，Eckert RL.莱菔硫烷减少雅普/Np 63 α信号传导以减少癌症干细胞存活和肿瘤形成。肿瘤靶向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PRMT 5/MEP 50功能，导致肿瘤形成减少。致癌作用2017;38：827-36。 12)Yagishita Y，Fahey JW，Dinkova-Kostova AT，Kensler TW.西兰花或萝卜硫素：重要的是剂量还是剂量？分子2019;24：3593 13)Yanaka A，Suzuki H，Mutoh M，Kamoshida T，Kakinoki N，Yoshida S，Hirose M，Ebihara T，Hyodo I.饮食摄入萝卜硫素对结肠癌的化学预防作用。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.表观遗传学/表观基因组学和异硫氰酸酯预防癌症的早期阶段。癌症预防研究2021;14：151-64