Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.
Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.
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DOI：
10.1136/gutjnl-2020-320946
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发表时间：
2021-03
期刊：
影响因子：
24.5
通讯作者：
Vilar E
中科院分区：
文献类型：
--
作者：
Reyes-Uribe L;Wu W;Gelincik O;Bommi PV;Francisco-Cruz A;Solis LM;Lynch PM;Lim R;Stoffel EM;Kanth P;Samadder NJ;Mork ME;Taggart MW;Milne GL;Marnett LJ;Vornik L;Liu DD;Revuelta M;Chang K;You YN;Kopelovich L;Wistuba II;Lee JJ;Sei S;Shoemaker RH;Szabo E;Richmond E;Umar A;Perloff M;Brown PH;Lipkin SM;Vilar E
林奇综合征（LS）患者患结直肠癌的风险显着增加。人们越来越认识到免疫系统在 LS 肿瘤的发展中起着至关重要的作用，从而成为癌症预防的理想目标。我们的目的是评估萘普生作为 LS 患者一级和二级化学预防的安全性、活性并发现涉及萘普生活性的新分子途径。我们对 80 名 LS 参与者进行了一项 Ib 期安慰剂对照随机临床试验，每天给予两种剂量水平的萘普生钠（440 和 220 mg），持续 6 个月，并使用 LS 和患者源性类器官 (PDO) 的基因工程小鼠模型进行了一项联合临床试验。总体而言，不同治疗组的不良事件总数没有差异，干预措施具有良好的耐受性。与安慰剂相比，萘普生治疗后结直肠粘膜中前列腺素 E2 的水平显着降低。萘普生激活了不同的常驻免疫细胞类型，而淋巴细胞结构没有任何增加，并改变了肠隐窝的表达模式，使其朝向上皮分化和干细胞调节。萘普生在小鼠联合临床试验中表现出强大的化学预防活性，并且萘普生在人类中诱导的基因表达谱显示出对经萘普生和对照处理的具有 LS 和 PDO 的小鼠样本的完美区分。萘普生是一种很有前途的 LS 免疫拦截策略。我们发现了萘普生诱导的基因表达谱，其可能用作药物活性的预测生物标志物。政府标识符：NCT02052908
Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. gov Identifier: NCT02052908
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影响因子：
168.9
作者：
Burn, John;Gerdes, Anne-Marie;Macrae, Finlay;Mecklin, Jukka-Pekka;Moeslein, Gabriela;Olschwang, Sylviane;Eccles, Diane;Evans, D. Gareth;Maher, Eamonn R.;Bertario, Lucio;Bisgaard, Marie-Luise;Dunlop, Malcolm G.;Ho, Judy W. C.;Hodgson, Shirley V.;Lindblom, Annika;Lubinski, Jan;Morrison, Patrick J.;Murday, Victoria;Ramesar, Raj;Side, Lucy;Scott, Rodney J.;Thomas, Huw J. W.;Vasen, Hans F.;Barker, Gail;Crawford, Gillian;Elliott, Faye;Movahedi, Mohammad;Pylvanainen, Kirsi;Wijnen, Juul T.;Fodde, Riccardo;Lynch, Henry T.;Mathers, John C.;Bishop, D. Timothy
通讯作者：
Bishop, D. Timothy
影响因子：
9
作者：
Nakanishi, Masako;Rosenberg, Daniel W.
通讯作者：
Rosenberg, Daniel W.
影响因子：
8.8
作者：
Buckland, M.;Jago, C. B.;Lombardi, G.
通讯作者：
Lombardi, G.
影响因子：
24.5
作者：
Møller P;Seppälä T;Bernstein I;Holinski-Feder E;Sala P;Evans DG;Lindblom A;Macrae F;Blanco I;Sijmons R;Jeffries J;Vasen H;Burn J;Nakken S;Hovig E;Rødland EA;Tharmaratnam K;de Vos Tot Nederveen Cappel WH;Hill J;Wijnen J;Green K;Lalloo F;Sunde L;Mints M;Bertario L;Pineda M;Navarro M;Morak M;Renkonen-Sinisalo L;Frayling IM;Plazzer JP;Pylvanainen K;Sampson JR;Capella G;Mecklin JP;Möslein G;Mallorca Group (http://mallorca-group.eu)
通讯作者：
Mallorca Group (http://mallorca-group.eu)
影响因子：
11.2
作者：
Spira A;Yurgelun MB;Alexandrov L;Rao A;Bejar R;Polyak K;Giannakis M;Shilatifard A;Finn OJ;Dhodapkar M;Kay NE;Braggio E;Vilar E;Mazzilli SA;Rebbeck TR;Garber JE;Velculescu VE;Disis ML;Wallace DC;Lippman SM
通讯作者：
Lippman SM