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.

家族性腺瘤性息肉病 (FAP) 和林奇综合征 (LS) 是遗传性结直肠癌 (CRC) 综合征，属于临床预防研究的高危人群。 FAP 是由种系 APC 突变引起的结肠息肉病和 CRC 易感综合征。结肠镜检查和预防性结肠切除术是标准治疗方法，而多项临床和动物研究已证明非甾体抗炎药 (NSAID) 具有化学预防功效。对于 FAP，尚无 FDA 批准用于该适应症的药物。 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 MLH1、MSH2、MSH6 和 PMS2 突变引起的。或在 EPCAM 中，导致 DNA MMR 缺陷并导致 70-80% 的终生罹患 CRC 的风险因此，FAP 和 LS 是明确定义的患者群体，终生 CRC 的发生率高达 90%。很可能从有效的结直肠癌化学预防中受益的风险。 欧米伽 (ω)-3 多不饱和脂肪酸，包括二十碳五烯酸 (EPA)，可抑制 ApcMin/+ 小鼠的肠息肉形成。在一项随机、双盲、安慰剂对照试验中，接受 EPA-FFA 治疗 6 个月的 FAP 患者结肠息肉数量和大小分别净减少 22% 和 30%。 EPA 的肿瘤抑制活性机制是其作为花生四烯酸 (AA) 氧合的竞争性抑制剂的能力，EPA-FFA 显着增加肠粘膜 EPA 含量，有效地取代膜磷脂中的 AA。环氧合酶 (COX) 和脂氧合酶 (LOX) 协同形成一系列复杂的生物活性脂质代谢产物。 AA（包括 PGE2）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。 FFA 快速氧化 EPA 的一种新型离子衍生物，L-赖氨酸二二十碳五烯酸镁 (TP-252)，其化学性质更稳定且更有效。 TP-252 抑制 PGE2 和其他促肿瘤代谢物，专门设计用于向肠粘膜输送治疗水平的 EPA-FFA，最近评估了 TP-252 在 NSAID 萘普生抑制 COX 方面的功效，并显示出对抗 CRC 的功效。在类风湿性关节炎、骨关节炎和幼年关节炎的临床前模型中，萘普生具有与阿司匹林相似的功效，但副作用较少。或吲哚美辛是提高 LS/HNPCC 小鼠存活率的最有效的非甾体抗炎药，Fishel 等人使用肠道和结肠直肠靶向 Msh2 缺失的 LS 小鼠模型测试了不同的非甾体抗炎药对饮食萘普生 (331 ppm) 的治疗效果。与 400 ppm 阿司匹林治疗相比，LS 小鼠的存活率几乎翻倍。这些临床前数据导致了 NCI-DCP 临床的启动。林奇综合征突变携带者萘普生的 Ib 期生物标志物联合研究试验 (NCT02052908) 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在两种高渗透性的啮齿动物遗传模型中减少 CRC 肿瘤负担； APC 突变大鼠 Pirc（模拟 FAP）和创新型新型 VcMsh2 小鼠（模拟 LS）。