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: 10020560
• 负责人: Clinton Grubbs
• 金额: $ 95.22万
• 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 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020560
• 关键词: Adenomatous Polyposis Coli; 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 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; Predisposition; Prevention; Property; Prostaglandin-Endoperoxide Synthase; Randomized; Rattus; Regimen; Rheumatoid Arthritis; Rodent; Structure; Syndrome; Testing; Therapeutic; Tissues; Tumor Burden; analog; cancer chemoprevention; colorectal cancer prevention; colorectal cancer risk; design; 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 VcMsh2Thu mouse that models LS.

家族性腺瘤性息肉病（FAP）和Lynch综合征（LS）是遗传性结直肠癌（CRC）综合征，是临床预防研究中可确定的高危人群。FAP是由生殖系APC突变引起的结肠息肉病和CRC易感综合征。频繁的结肠镜检查和预防性结肠切除术是治疗的标准。虽然一些临床和动物研究已经证明了非甾体抗炎药（NSAID）对FAP的化学预防功效，但没有FDA批准的药物用于该适应症。LS是最常见的遗传性CRC综合征，影响超过100万美国人。LS是由错配修复（MMR）基因MLH 1、MSH 2、MSH 6和PMS 2或EPCAM中的突变引起的，导致DNA MMR缺陷，并赋予70-80%的发展CRC的终身风险。因此，FAP和LS是明确定义的患者人群，其具有高达90%的终生CRC风险，极有可能从有效的CRC化学预防中获益。 欧米茄（ω）-3多不饱和脂肪酸，包括二十碳五烯酸（EPA），抑制肠息肉形成。含有游离脂肪酸形式的EPA（EPA-FFA）的饮食减少了ApcMin/+小鼠中的息肉负担。重要的是，在一项随机、双盲、安慰剂对照试验中，用EPA-FFA治疗FAP患者6个月，结肠息肉数量和大小净减少22%和30%。EPA的肿瘤抑制活性的潜在机制是其作为花生四烯酸（AA）氧化的竞争性抑制剂的能力。EPA-FFA显著增加肠粘膜EPA含量，有效地从膜磷脂中置换AA。AA和EPA都充当环加氧酶（COX）和脂氧合酶（LOX）的底物，所述环加氧酶和脂氧合酶在生物活性脂质代谢物的复杂阵列的形成中协作。由AA形成的几种代谢产物，包括PGE 2，与CRC促进密切相关。然而，AA和EPA之间的微小结构差异改变了许多脂质代谢物的合成，这有助于ω-3 PUFA的肿瘤抑制特性。然而，高纯度EPA-FFA迅速氧化。EPA的新型离子衍生物，L-赖氨酸二二十碳五烯酸镁（TP-252），其化学上更稳定并且在抑制PGE 2和其他促肿瘤代谢物方面更有效，被专门设计用于将治疗水平的EPA-FFA递送至肠粘膜。最近在ApcΔ14/+小鼠中评价了TP-252的疗效。NSAID naclofen抑制COX，并在临床前模型中显示出对CRC的益处。在类风湿性关节炎、骨关节炎和青少年关节炎的临床研究中，萘普生的疗效与阿司匹林或吲哚美辛相似，但副作用较少。萘普生是提高LS/HNPCC小鼠存活率最有效的NSAID。使用肠和结肠直肠靶向Msh 2缺失LS小鼠模型，Fishel等人测试了不同NSAID对LS模型存活率的影响。与400 ppm阿司匹林治疗相比，用膳食萘普生（331 ppm）治疗几乎使LS小鼠存活率加倍。这些临床前数据导致NCI-DCP临床联盟研究启动了Lynch综合征突变携带者中的NaBpen Ib期生物标志物试验（NCT 02052908）。该项目的总体目标是评估TP-252单独使用或与萘普生联合使用是否会降低两种啮齿动物遗传模型中的CRC肿瘤负荷;一种高度渗透的APC突变大鼠Pirc，模拟FAP，以及一种创新的新型VcMsh 2 Thu小鼠，模拟LS。