Dietary methionine restriction as a therapeutic strategy for metastatic melanoma

饮食蛋氨酸限制作为转移性黑色素瘤的治疗策略

基本信息

批准号：
10090751
负责人：
Isabelle Racine Miousse
金额：
$ 23.11万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
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：
2021-04-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10090751
关键词：
Adjuvant Adopted Affect American Animal Model Animals Antibodies Arkansas Autophagocytosis Bacterial DNA Bioenergetics Body Weight CTLA4 gene Cells Centers of Research Excellence Cessation of life Clinical Trials Data Data Analyses Data Science Development Diet Disease Disease remission Exposure to Flow Cytometry Germ-Free Goals Growth Homocysteine Image Imaging Device Immune checkpoint inhibitor Immune system Immunocompetent Literature Liver Lung Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Mentors Metabolic Metabolic Pathway Metabolism Metastatic Melanoma Metastatic Neoplasm to the Lung Metastatic to Methionine Mitochondria Modeling Molecular Monoclonal Antibodies Mus Neoplasm Metastasis Nivolumab Normal Cell Pathway interactions Patients Persons Population Proteomics Reactive Oxygen Species Research Research Personnel Resistance Resources Role Sampling Source Spectrum Analysis Testing Therapeutic Tissues Tumor-Infiltrating Lymphocytes Work bone cancer cell checkpoint therapy dietary dietary restriction experimental study fecal transplantation gut microbiome gut microbiota immune checkpoint immune checkpoint blockade in vivo imaging insight ipilimumab melanoma microbiome microbiome alteration mitochondrial dysfunction mortality mouse model novel strategies novel therapeutic intervention pembrolizumab pre-clinical programmed cell death protein 1 repaired spectroscopic imaging standard of care tumor

项目摘要

Project Summary – Project Leader Isabelle Racine Miousse Nearly 10,000 Americans die from melanoma every year. Since 2011, immune checkpoint inhibitors have been approved for metastatic melanoma. These antibodies enhance a person’s immune system ability to recognize cancer cells. Despite a major improvement in remission rates, the majority of patients do not respond to immune checkpoint inhibitors. The identification of approaches to overcome immune checkpoint inhibitor resistance, as well as new therapeutic strategies to treat metastatic melanoma, are crucially needed. Cancer cells rely on exogenous sources of methionine, contrarily to normal cells that can thrive off the remethylation of homocysteine. Our data shows that at levels that maintain body weight, a methionine restricted diet dramatically reduces tumor size and number of lung metastases in an immunocompetent murine melanoma model. Our preliminary data indicates that the effect involves mitochondrial function. Recent work highlighted the importance of mitochondrial function in immune checkpoint inhibitor responders versus nonresponders. The combination of methionine restriction and immune checkpoint inhibitor responsiveness has never been tested. In addition to direct effects on methionine dependent cancer cells, we have determined that alterations in dietary methionine affect the gut microbiome. It is now well-established that there are significant differences in the gut microbiomes of patients with metastatic melanoma that are associated with efficacy of immune checkpoint inhibitor therapy, and that responsiveness can be induced with fecal transplantation in animal models. However, the impact of a methionine-regulated microbiome on melanoma growth, metastasis, and immune checkpoint inhibitor responsiveness is unknown. According to our data and supporting scientific literature, we hypothesize that dietary methionine restriction will promote antitumor mechanisms, including autophagy and microbiome alterations, which will increase immune checkpoint inhibitor responsiveness for metastatic melanoma. To test this hypothesis, we propose to study the effect of a methionine restricted diet in a preclinical, immunocompetent mouse model of melanoma. Following establishment of tumor, mice will receive a standard diet or an identical diet containing low levels of methionine to investigate the following: Aim 1) Determine whether methionine restriction increases responsiveness to immune checkpoint blockade in a preclinical mouse model. Aim 2) Determine the contribution of gut microbiota in methionine-dependent antitumor activity. Our study investigates a novel approach to decrease mortality due to metastatic melanoma. We expect the results generated from our studies to be translatable to other types of malignancies, especially those for which immune checkpoint inhibitors are used for therapy.

项目摘要 - 项目负责人Isabelle Racine Mousse 每年将近10,000名美国人死于黑色素瘤。自2011年以来，免疫抑制剂具有他们被批准用于转移性黑色素瘤。这些抗体增强了一个人的免疫系统能力识别癌细胞。尽管缓解率有重大提高，但大多数患者却没有反应进行免疫切除剂抑制剂。识别克服免疫切除剂抑制剂的方法至关重要的是，耐药性以及治疗转移性黑色素瘤的新治疗策略至关重要。癌细胞依赖于甲基氨酸的外源性来源，相反，正常细胞可以从同型半胱氨酸的再生甲基化。我们的数据表明，在维持体重的水平上，甲糖氨酸受限饮食大大减少了免疫能力的鼠类黑色素瘤中肿瘤的大小和肺转移数量模型。我们的初步数据表明效果涉及线粒体功能。最近的工作强调了线粒体功能在免疫检查点抑制剂反应者与非反应器中的重要性。蛋氨酸限制和免疫抑制剂反应的组合从未被测试过。除了直接对甲糖氨酸依赖性癌细胞的影响，我们还确定了饮食的改变甲基氨酸会影响肠道微生物组。现在良好的肠道有显着差异与免疫检查点有关的转移性黑色素瘤患者的微生物组抑制剂疗法，并且可以通过动物模型中的粪便移植来诱导反应能力。然而，甲烷瘤调节的微生物组对黑色素瘤生长，转移和免疫切除点的影响抑制剂响应能力尚不清楚。根据我们的数据和支持科学文献，我们假设饮食方法限制了将促进抗肿瘤机制，包括自噬和微生物组改变，这将增加免疫检查点抑制剂的转移性黑色素瘤反应能力。为了检验这一假设，我们建议研究了蛋氨酸受限饮食在临床前，免疫能力的小鼠模型中的影响。建立肿瘤后，小鼠将获得标准饮食或相同含有低水平的饮食方法以研究以下各种方法：目标1）确定方法限制是否增加临床前小鼠模型中对免疫切解点的反应。目标2）确定贡献肠道微生物群在甲基氨酸依赖性抗肿瘤活性中。我们的研究调查了一种新的方法，可降低由于转移性黑色素瘤而导致的死亡率。我们期望从我们的研究产生的结果可以转化为其他类型的恶性肿瘤，尤其是那些免疫检查点抑制剂用于治疗。