The role of dietary copper in melanoma

 描述(申请人提供)：一半的黑色素瘤编码致癌突变的BRAFV600E激酶，它使MEK1/2激酶磷酸化，进而使ERK1/2磷酸化，从而激活MAPK途径促进黑色素瘤的发生。针对突变的BRAF的变构ATP抑制剂使这种疾病的治疗发生了革命性的变化，在突变的BRAF阳性侵袭性疾病的患者中提供了超过一半的治疗反应。然而，患者总是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途径。在这方面，针对MAPK途径的MEK1/2激酶的变构ATP抑制剂已被证明在临床上增强了BRAF抑制剂的抗肿瘤作用。因此，MEK1/2是治疗BRAF阳性的晚期黑色素瘤的临床有效靶点。抑制ATP并不是靶向MEK1/2的唯一方法。具体地说，我们发现饮食中的铜(Cu)是这两种酶的辅助因素。此外，我们还发现，降低主要的铜转运蛋白CTR1的表达或突变MEK1上的铜结合部位可以抑制BRAFV600E阳性肿瘤细胞系的肿瘤生长。重要的是，肝豆状核变性患者的高铜水平在临床上可以通过降铜药物降低。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，并延长了经基因工程处理后发展为转移性黑色素瘤的小鼠的寿命。因此，TM是一种MEK1/2抑制剂，其作用机制完全不同于目前这些酶的变构ATP抑制剂。基于这些新数据，我们启动了一项临床癌症试验(NCT02068079)，以测试铜螯合剂和BRAF抑制剂在BRAF突变阳性的晚期黑色素瘤患者中的组合。鉴于这些进展，我们重新制定了A1拨款，现在将重点放在下一个最具临床相关性和紧迫性的问题上，即确定实施铜螯合的最有效的癌症环境(目标1)，并改进铜螯合剂的抗肿瘤活性(目标2)。因此，这些目标的完成将决定如何最好地利用铜螯合作为一种抑制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，以改进铜络合剂，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.