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BRAFV 600 E激酶，其磷酸化MEK 1/2激酶，进而磷酸化ERK 1/2，从而激活MAPK通路以促进黑色素瘤。突变型BRAF特异性变构ATP抑制剂彻底改变了这种疾病的治疗，在超过一半的突变型BRAF阳性侵袭性疾病患者中提供了治疗反应。然而，患者总是对这些抑制剂产生耐药性，通常是通过各种遗传变化重新激活MAPK途径。在这方面，针对MAPK途径的MEK 1/2激酶的变构ATP抑制剂已被证明在临床上增强BRAF抑制剂的抗肿瘤作用。因此，MEK 1/2是用于治疗BRAF阳性晚期黑素瘤的临床验证的靶标。抑制ATP并不是靶向MEK 1/2的唯一途径。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CTR 1的表达或突变MEK 1上的铜结合位点可抑制BRAFV 600 E阳性肿瘤细胞系的肿瘤生长。重要的是，威尔逊病患者的高铜水平在临床上用铜还原药物降低。令人兴奋的是，用这些药物之一TM治疗小鼠，减少了BRAFV 600 E阳性肿瘤细胞系的肿瘤生长，延长了基因工程小鼠的寿命，从而发展出转移性黑色素瘤。因此，TM是一种MEK 1/2抑制剂，其具有与这些酶的当前变构ATP抑制剂根本不同的全新作用机制。基于这些新数据，我们启动了一项临床癌症试验（NCT 02068079），以测试铜螯合剂与BRAF抑制剂对BRAF突变阳性晚期黑色素瘤患者的联合作用。鉴于这些进展，我们重新制定了A1资助，现在专注于下一个最临床相关和紧迫的问题，即确定最有效的癌症环境以实施Cu螯合（目标1）和改善Cu螯合剂的抗肿瘤活性（目标2）。因此，这些目标的完成将确定如何最好地利用Cu螯合的优势作为抑制MEK 1/2的手段来治疗BRAF突变阳性的晚期黑素瘤，并开发一系列新的治疗方法，以改善Cu螯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.