Reducing dietary copper for the treatment of BRaf mutation-positive melanoma

描述（由申请人提供）：虽然饮食与癌症之间的关系已经被认识了几十年，但确定特定饮食干预与改善癌症结果之间的明确联系仍然是一个挑战。在确定生物活性食物成分的实际分子靶点方面，我们注意到一半的黑色素瘤编码致癌突变体BRAfV 600 E激酶，该激酶磷酸化Mek 1/2激酶，进而磷酸化Erk 1/2，从而激活MAPK通路促进黑色素瘤。靶向Mek 1/2被证明是与BRaf激酶抑制剂联合治疗黑色素瘤的一种有前途的策略。然而，Mek 1/2激酶抑制剂仍处于临床开发阶段，其长期安全性仍有待确定，其无疑的高成本将成为患者获取的障碍。作为一种替代策略，我们发现膳食铜对Mek 1/2的激酶活性至关重要。此外，敲低表达的主要铜转运蛋白Ctr 1或cytokine降低铜水平抑制肿瘤生长的BRafV 600 E阳性细胞系。这提出了一个令人兴奋的可能性，即减少饮食中的铜可能对治疗黑色素瘤有治疗价值。因此，我们在AIM 1中提出了一个基本的研究路线，以确定基因切除Ctr 1基因对Mek 1/2活性，肿瘤发生和转移性黑色素瘤小鼠生存的影响。我们还提出了一个翻译线的研究在AIM 2中，以确定一个药理学铜限制策略，提供了一个生存优势，小鼠发展转移性黑色素瘤。这些目标的完成将评估操纵膳食铜治疗黑色素瘤的潜在功效，这可以作为这种治疗这种癌症的新治疗策略的临床试验开发的基础。

DESCRIPTION (provided by applicant): While a relationship between diet and cancer has been appreciated for decades, identifying definitive links between specific dietary interventions and improved cancer outcomes has remained a challenge. In terms of identifying an actual molecular target for bioactive food components, we note that 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. Targeting Mek1/2 is proving to be a promising strategy to treat melanoma when combined with BRaf kinase inhibitors. However, Mek1/2 kinase inhibitors are still in clinical development, their long-term safety profiles remain o be determined, and their undoubtedly high cost will be a barrier to patient access. As an alternative strategy, we discovered that dietary copper is critical for the kinase activity of Mek1/2. Moreover, knocking down the expression of the primary copper transporter Ctr1 or pharmacologically reducing copper levels inhibited tumorigenic growth of BRafV600E-positive cell lines. This raises the exciting possibility that reducing dietary copper could have therapeutic value in the treatment of melanoma. We therefore propose in AIM 1 a basic line of investigation to determine the impact of genetically ablating the Ctr1 gene on Mek1/2 activity, tumorigenesis, and survival of mice developing metastatic melanoma. We also propose a translational line of investigation in AIM 2 to identify a pharmacological copper-restriction strategy that provides a survival advantage to mice developing metastatic melanoma. Completion of these aims will evaluate the potential efficacy of manipulating dietary copper for the treatment of melanoma, which could serve as the basis for clinical trial development of this novel therapeutic strategy fo the treatment of this cancer.