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 Miousse 自 2011 年以来，免疫检查点抑制剂每年有近 10,000 名美国人死于黑色素瘤。这些抗体已被批准用于治疗转移性黑色素瘤。尽管缓解率显着提高，但大多数患者没有反应。免疫检查点抑制剂的识别克服免疫检查点抑制剂的方法。迫切需要耐药性以及治疗转移性黑色素瘤的新治疗策略。癌细胞依赖于外源性蛋氨酸，这与正常细胞相反，正常细胞可以依靠蛋氨酸而茁壮成长。我们的数据表明，在维持体重的水平上，蛋氨酸受到限制。饮食可显着减少免疫活性小鼠黑色素瘤的肿瘤大小和肺转移瘤的数量我们的初步数据表明，这种影响涉及线粒体功能。线粒体功能在免疫检查点抑制剂应答者与无应答者中的重要性。蛋氨酸限制和免疫检查点抑制剂反应性的组合从未经过测试。除了对蛋氨酸依赖性癌细胞产生直接影响外，我们还确定饮食的改变蛋氨酸影响肠道微生物群，现已证实肠道存在显着差异。转移性黑色素瘤患者的微生物组与免疫检查点的功效相关抑制剂疗法，并且可以通过动物模型中的粪便移植来诱导反应性。蛋氨酸调节的微生物组对黑色素瘤生长、转移和免疫检查点的影响抑制剂反应性未知。根据我们的数据和支持科学文献，我们发现饮食蛋氨酸限制将促进抗肿瘤机制，包括自噬和微生物组改变，这将增加免疫检查点抑制剂对转移性黑色素瘤的反应性为了检验这一假设，我们建议研究蛋氨酸限制饮食对临床前免疫功能正常的黑色素瘤小鼠模型的影响。肿瘤形成后，小鼠将接受标准饮食或含有低水平的相同饮食蛋氨酸来研究以下内容：目标 1) 确定蛋氨酸限制是否增加临床前小鼠模型对免疫检查点阻断的反应目标 2) 确定贡献。肠道微生物群在蛋氨酸依赖性抗肿瘤活性中的作用。我们的研究调查了一种降低转移性黑色素瘤死亡率的新方法。我们的研究结果可以转化为其他类型的恶性肿瘤，特别是那些免疫检查点抑制剂用于治疗。