The role of dietary copper in melanoma

膳食铜在黑色素瘤中的作用

• 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
• 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

 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.

 描述（由适用提供）：一半的黑色素瘤编码了一种致癌突变体BRAFV600E激酶，该激酶磷酸化MEK1/2激酶和ERK1/2依次磷酸化，从而激活了MAPK途径以促进黑色素瘤。特异性突变体BRAF的变构ATP抑制剂已彻底改变了该疾病的治疗，为超过一半的突变体BRAF阳性侵袭性疾病的患者提供了治疗反应。但是，患者总是通过各种遗传变化对MAPK途径重新激活，通常通过对这些抑制剂产生抗性。在这方面，已证明针对MAPK途径的MEK1/2激酶的变构ATP抑制剂已显示可在临床上增强BRAF抑制剂的抗肿瘤作用。这是MEK1/2是临床验证的靶标，用于治疗BRAF阳性晚期黑色素瘤。抑制ATP并不是针对MEK1/2的唯一方法。特别是，我们发现饮食铜（CU）是这两种酶的共同因素。此外，我们还发现，降低原代Cu转运蛋白CTR1的表达或在MEK1上突变Cu结合位点抑制BRAFV600E阳性肿瘤细胞系的肿瘤生长。重要的是，威尔逊氏病患者的CU水平高临床减少CU减少药物。令人兴奋的是，用其中一种TM治疗小鼠，降低了BRAFV600E阳性肿瘤细胞系的肿瘤生长，并延长了促进转移性黑色素瘤的小鼠的寿命。 TM是一种MEK1/2抑制剂，具有完全新颖的作用机理，与这些酶的当前ATP抑制剂根本不同。基于这些新数据，我们启动了一项临床癌症试验（NCT02068079），以测试Cu螯合剂与BRAF抑制剂在BRAF突变阳性后期黑色素瘤患者中的组合。鉴于这些进展，我们已经重新制定了A1赠款，现在将重点放在下一个临床上最相关且紧迫的问题上，即确定最有效的癌症环境以实施CU螯合（AIM 1），并改善CU螯合子的抗抑制活性（AIM 2）。因此，这些目标的完成将确定如何最好地利用Cu螯合的优势，以此作为抑制MEK1/2治疗BRAF突变阳性，晚期黑色素瘤的手段，并开发出一种新型治疗方法的渠道，从而改善CU螯合剂的未来临床分析。

项目成果

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
• 作者: Xu M;Casio M;Range DE;Sosa JA;Counter CM
• 通讯作者: Counter CM