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The role of dietary copper in melanoma

膳食铜在黑色素瘤中的作用

基本信息

批准号：
9767706
负责人：
CHRISTOPHER M COUNTER
金额：
$ 35.28万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767706
关键词：
Agreement Ammonium Antineoplastic Agents BRAF gene Binding Sites Cell Line Cells Chelating Agents Clinical Clinical Trials Data Dietary Copper Disease Dose Drug Addiction Drug usage Enzyme Inhibitor Drugs Enzymes Future Generations Genetically Engineered Mouse Grant Growth Hepatolenticular Degeneration Human Journals Longevity MAP Kinase Gene MAP2K1 gene MAPK3 gene Malignant Neoplasms Melanoma Cell Metals Metastatic Melanoma Mitogen-Activated Protein Kinase Kinases Mus Mutate Mutation Nature Oncogenic Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Public Health Publishing Resistance Resistance development Role Testing Tumor Cell Line base cancer clinical trial chelation clinically relevant drug development improved inhibitor/antagonist melanoma mutant novel novel therapeutic intervention novel therapeutics public health relevance research clinical testing response tetrathiomolybdate treatment response tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Half of melanomas encode an oncogenic mutant BRAFV600E kinase, which phosphorylates MEK1/2 kinases and in turn ERK1/2, thereby activating the MAPK pathway to promote melanoma. Allosteric ATP inhibitors specific to mutant BRAF have revolutionized the treatment of this disease, providing a therapeutic response in more than half of patients with mutant BRAF-positive aggressive disease. However, patients invariably develop resistance to these inhibitors, typically through reactivation of the MAPK pathway through a variety of genetic changes. In this regard, an allosteric ATP inhibitor against MEK1/2 kinase of the MAPK pathway has been shown to clinically enhance the anti-neoplastic effects of a BRAF inhibitor. Thus, MEK1/2 are clinically validated targets for the treatment of BRAF-positive late stage melanoma. Inhibiting ATP is not the only way to target MEK1/2. Specifically, we discovered that dietary copper (Cu) is a co-factor for these two enzymes. Moreover, we also found that reducing expression of the primary Cu transporter CTR1 or mutating the Cu-binding sites on MEK1 inhibits the tumor growth of BRAFV600E-positive tumor cell lines. Importantly, high Cu levels in patients with Wilson's disease are clinically lowered wih Cu-reducing drugs. Excitingly, treatment of mice with one of these drugs, TM, reduced the tumor growth of BRAFV600E-positive tumor cell lines and extended the lifespan of mice genetically engineered to develop metastatic melanoma. Thus, TM is a MEK1/2 inhibitor that has a completely novel mechanism of action that is fundamentally different from current allosteric ATP inhibitors of these enzymes. Based on these new data, we initiated a clinical cancer trial (NCT02068079) to test the combination of a Cu chelator with a BRAF inhibitor on BRAF mutation-positive, late stage melanoma patients. Given these advances, we have reformulated the A1 grant to now focus on the next most clinically relevant and pressing issues, namely identifying the most effective cancer settings to implement Cu chelation (aim 1) and improving upon the anti- neoplastic activity of Cu chelators (aim 2). Completion of these aims will thus determine how best to capitalize upon the advantages of Cu chelation as a means to inhibit MEK1/2 for the treatment of BRAF mutation-positive, late stage melanoma, and develop a pipeline of novel therapeutic approaches that improve upon Cu chelators for future clinical analysis.

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer.

DOI：
10.1158/1078-0432.ccr-17-3705
发表时间：
2018-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Xu M;Casio M;Range DE;Sosa JA;Counter CM
通讯作者：
Counter CM