Targeting vulnerabilities in copper metabolism in the development of cancer therapies

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PROJECT SUMMARY Although there have been important advances in the detection and treatment of cancer, there remains an urgent need to develop new therapeutic strategies. Copper (Cu) is an essential micronutrient that is required in higher amounts by cancer cells relative to normal tissues. Several enzymes with key roles in cancer require Cu for their activity, including lysyl oxidases and several oncogenic kinases (e.g., MEK1; ULK1). In pre-clinical models of cancer, many studies have shown that tumor growth and metastasis is suppressed by Cu chelators added to the diet. In clinical trials, Cu depletion via an oral Cu chelator was found to significantly slow disease progression in patients with mesothelioma, and significantly extend survival in breast cancer patients. While it is clear that Cu depletion is a promising anticancer strategy, there is a need to develop therapies that specifically target pathways of Cu delivery to oncogenic enzymes. In the current proposal, we pursue a highly innovative approach by targeting the Cu transporter, ATP7A. Our extensive preliminary studies validate ATP7A as a therapeutic target including: 1) Intestine-specific deletion of murine ATP7A lowers systemic copper status to levels shown to be therapeutic in cancer patients; 2) ATP7A is required to deliver copper to the family of lysyl oxidases, which have well-documented roles in metastasis; 3) Targeted deletion of ATP7A in breast and lung cancer cell lines reduces primary tumor growth and metastasis in mice; 4) Elevated ATP7A expression is significantly correlated with lower survival in cancer patients. Based on these findings, we hypothesize that a small molecule inhibitor of ATP7A will be therapeutic in cancer. Using computer-aided drug design, we have identified a hit molecule called MKV3 that binds to ATP7A with nanomolar affinity and inhibits ATP7A activity in cancer cell lines. Mice treated with MKV3 showed reduced activity of the serum Cu biomarker, ceruloplasmin, and reduced tumor growth. In this proposal, we will conduct structure guided optimization to identify MKV3 analogs with improved potency and drug like properties (Aim 1); conduct pharmacokinetic studies to identify MKV3 analogs that are suitable for pharmacodynamic studies (Aim 2); and evaluate the most favorable MKV3 analog in mouse models of breast cancer (Aim 3).