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.
Over 70,000 Americans will be diagnosed with melanoma this year. Thus, the proposed study to evaluate whether drugs used to reduce copper levels increase the survival of mice with melanoma has direct significance to human health, especially as results from these studies could be immediately implemented in a clinical setting for the treatment of this cancer.
|Brady, Donita C; Crowe, Matthew S; Turski, Michelle L et al. (2014) Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509:492-6|