Efficacy of an Electrophile Scavenger in the Prevention of Gastrointestinal Inflammatory Carcinogenesis

亲电子清除剂在预防胃肠道炎症癌发生中的功效

基本信息

  • 批准号:
    10257862
  • 负责人:
  • 金额:
    $ 40万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-09 至 2023-09-30
  • 项目状态:
    已结题

项目摘要

SUMMARY: Many cancers are recognized to have an inflammatory etiology. Gastric cancer, the third leading cause of cancer deaths worldwide, is the prototype- it is caused by infection with the bacterial pathogen Helicobacter pylori in 90% of cases. For colorectal cancer (CRC), the second leading cause of cancer deaths, inflammatory bowel disease (IBD) is a frequent precursor lesion. This STTR Phase I proposal is a partnership between the Wilson Lab at Vanderbilt University Medical Center (VUMC), which is focused on gastrointestinal inflammation- associated carcinogenesis, and MTI BioTech, Inc. (MTI), who are together developing a new therapeutic strategy to prevent cancer. Under conditions of chronic mucosal inflammation, increased enzyme activities result in formation of dicarbonyl electrophiles, products of lipid peroxidation that include isolevuglandins (isoLGs), malondialdehyde, 4-oxo-nonenal, and acrolein, all of which can form adducts with DNA, histones, and proteins. This adduct formation may lead to somatic genomic abnormalities and risk for neoplastic transformation. The compound 2-hydroxybenzylamine (2-HOBA) can serve as a scavenger of all electrophiles, thus preventing adduct formation. 2-HOBA is a natural product derived from buckwheat seeds. It has been shown to be highly bioavailable, with no toxicity, in rodents and in recent human Phase I clinical trials. 2-HOBA protects mice from oxidative damage in models of hypertension and Alzheimer’s disease. The Wilson Lab has discovered that isoLG adducts are increased i) in gastric tissues of patients and mice infected with H. pylori; ii) in the colon of humans with chronic colitis from inflammatory bowel disease, and colitis-associated cancer (CAC), and mice treated with azoxymethane-dextran sulfate sodium (AOM-DSS), a model of CAC. The Lab has found that a 2-HOBA analog, EtHOBA, which also scavenges electrophiles, markedly reduces gastric dysplasia and carcinoma in two models of H. pylori-induced gastric carcinoma, transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils, and reduces colonic tumorigenesis in the AOM-DSS CAC model. However, unlike 2-HOBA, EtHOBA has not reached development for human use. We hypothesize that electrophiles have a key role in inflammation-driven gastrointestinal carcinogenesis via formation of adducts to macromolecules and are new molecular targets for cancer prevention by 2-HOBA. We will determine the protective effect of 2-HOBA on H. pylori-induced gastric carcinogenesis in INS-GAS mice and gerbils (Aim 1) and on colitis-associated carcinogenesis in the AOM-DSS mouse model (Aim 2). Primary endpoints will be reduction in dysplasia, carcinoma, and tumor formation, and secondary endpoints will be effects on DNA damage and isoLG adducts. A successful STTR Phase I outcome will be a protective effect of 2-HOBA on gastric and colon carcinogenesis and will be the primary go/no go endpoint to a Phase II STTR project. We envision future studies testing 2-HOBA in animals in which disease is already fully established; further assessment of molecular mechanisms underlying protective effects, including in human organoids; and human clinical trials in patients with precancerous gastric and colon lesions.
简介:

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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John A Rathmacher其他文献

Post-prandial amino acid and leucine responses to serum albumin concentrate compared to whey protein concentrate in healthy subjects
Effects of 12 weeks of beta-hydroxy-beta-methylbutyrate free acid, adenosine triphosphate, or a combination on muscle mass, strength, and power in resistance trained individuals
  • DOI:
    10.1186/1550-2783-10-s1-p17
  • 发表时间:
    2013-12-06
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Ryan P Lowery;Jordan Joy;John A Rathmacher;Shawn M Baier;John C Fuller;Ralf Jäger;Stephanie M C Wilson;Jacob M Wilson
  • 通讯作者:
    Jacob M Wilson
Oral ATP administration improves blood flow response to exercise in an animal model and in resistance trained athletes
  • DOI:
    10.1186/1550-2783-10-s1-p16
  • 发表时间:
    2013-12-06
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Ryan P Lowery;Michael D Roberts;Frank W Booth;Jordan Joy;Clayton L Cruthirds;John A Rathmacher;Shawn M Baier;John C Fuller;Christopher M Lockwood;Ralf Jäger;Joshua E Dudeck;Jacob M Wilson
  • 通讯作者:
    Jacob M Wilson

John A Rathmacher的其他文献

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{{ truncateString('John A Rathmacher', 18)}}的其他基金

2-HOBA for Treatment of Pulmonary Hypertension
2-HOBA 治疗肺动脉高压
  • 批准号:
    10698621
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
2-HOBA for Treatment of Pulmonary Hypertension
2-HOBA 治疗肺动脉高压
  • 批准号:
    10257863
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans
2-羟基苄胺预防阿尔茨海默病:对人类的初步评估
  • 批准号:
    9970647
  • 财政年份:
    2016
  • 资助金额:
    $ 40万
  • 项目类别:
2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans
2-羟基苄胺预防阿尔茨海默病:对人类的初步评估
  • 批准号:
    9564351
  • 财政年份:
    2016
  • 资助金额:
    $ 40万
  • 项目类别:
Gamma-ketoaldehyde scavengers for alcoholic liver disease
γ-酮醛清除剂治疗酒精性肝病
  • 批准号:
    8834691
  • 财政年份:
    2014
  • 资助金额:
    $ 40万
  • 项目类别:
Nutritional Intervention for Age-Related Muscular Function and Strength Losses
针对与年龄相关的肌肉功能和力量损失的营养干预
  • 批准号:
    7909359
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:
Nutritional Intervention for Age-Related Muscular Function and Strength Losses
针对与年龄相关的肌肉功能和力量损失的营养干预
  • 批准号:
    9515437
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:
Nutritional Intervention for Age-Related Muscular Function and Strength Losses
针对与年龄相关的肌肉功能和力量损失的营养干预
  • 批准号:
    8775460
  • 财政年份:
    2010
  • 资助金额:
    $ 40万
  • 项目类别:
Adjuvant Nutrition for Critically III Trauma Patients
危重 III 级创伤患者的辅助营养
  • 批准号:
    6582697
  • 财政年份:
    2003
  • 资助金额:
    $ 40万
  • 项目类别:
BODY PROTEIN METABOLISM & NUTRITION IN AIDS WASTING
身体蛋白质代谢
  • 批准号:
    6977108
  • 财政年份:
    2003
  • 资助金额:
    $ 40万
  • 项目类别:

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Acrolein调控耳蜗核神经元-胶质细胞网络参与感音神经性耳聋发病机制的研究
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