The role of dietary copper in melanoma

 描述（由申请人提供）：一半的黑色素瘤编码致癌突变体 BRAFV600E 激酶，该激酶磷酸化 MEK1/2 激酶，进而磷酸化 ERK1/2，从而激活 MAPK 途径以促进黑色素瘤。针对突变 BRAF 的变构 ATP 抑制剂彻底改变了这种疾病的治疗，为一半以上患有突变 BRAF 阳性侵袭性疾病的患者提供了治疗反应。然而，患者总是会对这些抑制剂产生耐药性，通常是通过各种基因变化重新激活 MAPK 通路。在这方面，针对 MAPK 途径 MEK1/2 激酶的变构 ATP 抑制剂已被证明可以在临床上增强 BRAF 抑制剂的抗肿瘤作用。因此，MEK1/2 是治疗 BRAF 阳性晚期黑色素瘤的临床验证靶点。抑制 ATP 并不是靶向 MEK1/2 的唯一方法。具体来说，我们发现膳食铜 (Cu) 是这两种酶的辅助因子。此外，我们还发现降低主要铜转运蛋白CTR1的表达或突变MEK1上的铜结合位点可以抑制BRAFV600E阳性肿瘤细胞系的肿瘤生长。重要的是，临床上可通过铜还原药物降低威尔逊氏病患者的高铜水平。令人兴奋的是，用其中一种药物 TM 治疗小鼠，减少了 BRAFV600E 阳性肿瘤细胞系的肿瘤生长，并延长了经过基因工程改造产生转移性黑色素瘤的小鼠的寿命。因此，TM 是一种 MEK1/2 抑制剂，具有全新的作用机制，与目前这些酶的变构 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 抑制剂的组合对 BRAF 突变阳性的晚期黑色素瘤患者的作用。鉴于这些进展，我们重新制定了 A1 资助计划，现在重点关注下一个与临床最相关和最紧迫的问题，即确定最有效的癌症环境来实施铜螯合（目标 1）并改善铜螯合剂的抗肿瘤活性（目标 2）。因此，完成这些目标将决定如何最好地利用铜螯合剂的优势作为抑制 MEK1/2 的手段来治疗 BRAF 突变阳性的晚期黑色素瘤，并开发一系列新的治疗方法来改进铜螯合剂以用于未来的临床分析。

 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.