Task Order: Colorectal Cancer Prevention by a Novel EPA Analogue TP-252 and Naproxen in FAP and lynch syndrome models

任务顺序：通过新型 EPA 类似物 TP-252 和萘普生在 FAP 和林奇综合征模型中预防结直肠癌

• 批准号: 10349404
• 负责人: GREGORY KENNEDY
• 金额: $ 55.42万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349404
• 关键词: APC mutation; Affect; American; Animals; ApcMin/+ mice; Arachidonic Acids; Aspirin; Biological Markers; Chemicals; Chemopreventive Agent; Chronic Childhood Arthritis; Clinical; Clinical Research; Colectomy; Colon; Colonic Polyps; Colonoscopy; Colorectal; Colorectal Cancer; Complex; DNA Sequence Alteration; Data; Degenerative polyarthritis; Diet; Dinoprostone; Dose; Eicosapentaenoic Acid; FDA approved; Familial Adenomatous Polyposis Syndrome; Familial colorectal cancer; Genetic Models; Germ Lines; Goals; Hereditary Nonpolyposis Colorectal Neoplasms; Indomethacin; Intestinal Mucosa; Intestinal Polyps; Intestines; Lipids; Lipoxygenase; MLH1 gene; MSH2 gene; MSH6 gene; Magnesium; Membrane; Metabolic; Minor; Mismatch Repair; Modeling; Mus; Mutation; Naproxen; Non-Steroidal Anti-Inflammatory Agents; Nonesterified Fatty Acids; Omega-3 Fatty Acids; Oxides; PMS2 gene; Patients; Pharmaceutical Preparations; Phase; Phospholipids; Plasma; Polyps; Pre-Clinical Model; Prevention; Property; Prostaglandin-Endoperoxide Synthase; Randomized; Rattus; Regimen; Rheumatoid Arthritis; Rodent; Structure; Syndrome; Testing; Therapeutic; Tissues; Tumor Burden; analog; cancer chemoprevention; cancer predisposition; colorectal cancer prevention; colorectal cancer risk; design; dietary; double-blind placebo controlled trial; gene repair; high risk population; inhibitor/antagonist; innovation; lifetime risk; mouse model; mutant; mutation carrier; novel; patient population; polyposis; pre-clinical; predictive marker; prophylactic; side effect; standard of care; tumor

Familial adenomatous polyposis (FAP) and Lynch syndrome (LS) are hereditary colorectal cancer (CRC) syndromes that are definable high-risk populations for clinical prevention studies. FAP is a colon polyposis and CRC predisposition syndrome caused by germ-line APC mutations. Frequent colonoscopy and prophylactic colectomy are standard of care. While several clinical and animal studies have demonstrated chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for FAP, there are no FDA-approved drugs for this indication. LS is the most common hereditary CRC syndrome, affecting >1 million Americans. LS is caused by mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2 or in EPCAM, resulting in deficient DNA MMR and confers 70-80% lifetime risk of developing CRC. Thus, FAP and LS are well defined patient populations with up to 90% lifetime CRC risk that are highly likely to benefit from effective CRC chemoprevention. Omega (ω)-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), suppress intestinal polyp formation. A diet containing the free fatty acid form of EPA (EPA-FFA) reduced polyp burden in ApcMin/+ mice. Importantly, treatment of FAP patients for 6 months with EPA-FFA showed 22% and 30% net reduction in colon polyp number and size, in a randomized, double-blinded, placebo-controlled trial. The underlying mechanism of the tumor-suppressive activity of EPA is its ability to act as a competitive inhibitor of arachidonic acid (AA) oxygenation. EPA-FFA significantly increases intestinal mucosal EPA content effectively displacing AA from membrane phospholipids. Both AA and EPA serve as substrates for the cyclooxygenases (COXs) and lipoxygenases (LOXs) that collaborate in the formation of a complex array of bioactive lipid metabolites. Several metabolic products formed from AA, including PGE2, are strongly associated with CRC promotion. However, minor structural differences between AA and EPA alter synthesis of many lipid metabolites, which contributes to the tumor-suppressive properties of the ω-3 PUFAs. However, high-purity EPA-FFA rapidly oxidizes. A novel ionic derivative of EPA, magnesium l-lysinate biseicosapentaenoate (TP-252), which is chemically more stable and more effective at inhibiting PGE2 and other tumor-promoting metabolites, is specifically designed to deliver therapeutic levels of EPA-FFA to the intestinal mucosa. Recently TP-252 was evaluated for its efficacy in ApcΔ14/+ mice. NSAID naproxen inhibits COXs and has shown benefit against CRC in preclinical models. In clinical studies for rheumatoid arthritis, osteoarthritis, and juvenile arthritis, Naproxen has similar efficacy but fewer side effects than aspirin or indomethacin. Naproxen is the most effective NSAID to increase survival of LS/HNPCC mice. Using an intestine and colorectum targeted Msh2 deletion LS mouse model, Fishel et al. tested different NSAIDs on LS model survival. Treatment with dietary naproxen (331 ppm) almost doubled LS mice survival compared to 400 ppm aspirin treatment. These preclinical data led to the initiation of NCI-DCP Clinical Consortium study Phase Ib Biomarker Trial of Naproxen in Lynch Syndrome Mutation Carrier (NCT02052908). The overall goal of the project is to evaluate whether TP-252 alone or in combination with naproxen will reduce CRC tumor burden in two rodent genetic models; a highly penetrant APC-mutant rat, Pirc, that models FAP, and an innovative novel VcMsh2 mouse that models LS.

家族性腺瘤多构（FAP）和林奇综合征（LS）是遗传性结直肠癌（CRC）综合征，是可确定的高风险人群，用于临床预防研究。 FAP是由种系APC突变引起的结肠多构和CRC倾向综合征。频繁的结肠镜检查和预防性收集术是护理标准。尽管几项临床和动物研究表明，非甾体类抗炎药（NSAIDS）的化学预防效率用于FAP，但没有FDA批准的药物来表明这种迹象。 LS是最常见的遗传性CRC综合征，影响了100万美国人。 LS是由不匹配修复（MMR）基因，MLH1，MSH2，MSH6和PMS2或EPCAM中的突变引起的，导致DNA MMR不足，并赋予70-80％的CRC终身风险。这是FAP和LS是明确定义的患者人群，其终身CRC风险高达90％，这很可能受益于有效的CRC化学预防。 Omega（ω）-3多不饱和脂肪酸，包括二十碳酸盐酸（EPA），抑制肠道息肉的形成。一种含有EPA（EPA-FFA）游离脂肪酸形式的饮食减少了APCMIN/+小鼠的息肉燃烧。重要的是，在一项随机的，双盲的，安慰剂对照试验中，用EPA-FFA治疗EPA-FFA 6个月的患者净减少了22％和30％。 EPA肿瘤抑制活性的基本机制是其充当蛛网膜酸（AA）氧合的竞争抑制剂的能力。 EPA-FFA显着增加了肠粘膜EPA含量有效地从膜磷脂中取代AA。 AA和EPA都是环氧酶（COXS）和Lipoxygyass（LOX）的底物，它们在形成复杂的生物活性脂质代谢物的复杂阵列中合作。由AA形成的几种代谢产物，包括PGE2，与CRC促进密切相关。但是，AA和EPA之间的较小结构差异改变了许多脂质代谢产物的合成，这有助于ω-3 PUFA的肿瘤抑制特性。但是，高纯度EPA-FFA迅速氧化。一种新型的EPA，L-赖氨酸二苯甲酸镁的离子衍生物（TP-252），在化学上更稳定，更有效地抑制PGE2和其他促进肿瘤的代谢物，是专门设计的，旨在将EPA-FFFA的治疗水平提供给肠道上的含量。最近，评估了TP-252在APCδ14/+小鼠中的有效性。 NSAID萘普生抑制COX，并在临床前模型中显示出对CRC的益处。在类风湿关节炎，骨关节炎和青少年关节炎的临床研究中，萘普生的有效性相似，但副作用却少于阿司匹林或吲哚美辛。萘普生是增加LS/HNPCC小鼠存活率的最有效的NSAID。 Fishel等人使用肠道和大肠靶向MSH2缺失LS小鼠模型。在LS模型存活下测试了不同的NSAID。与400 ppm阿司匹林治疗相比，用饮食中的萘普生（331 ppm）的治疗几乎翻了一番。这些临床前数据导致了NCI-DCP临床联盟研究阶段IB生物标志物试验lynch综合征突变载体（NCT02052908）的倡议。该项目的总体目标是评估TP-252是否单独或与萘普生结合使用将减少两个啮齿动物遗传模型中的CRC肿瘤伯嫩；高度渗透性的APC突变大鼠PIRC，模拟FAP，以及一种创新的新型VCMSH2小鼠，该小鼠对LS进行了建模。