# Targeting vulnerabilities in copper metabolism in the development of cancer therapies

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $441,538

## Abstract

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).

## Key facts

- **NIH application ID:** 10897180
- **Project number:** 5R01CA262664-04
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** MICHAEL J. PETRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,538
- **Award type:** 5
- **Project period:** 2021-08-03 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897180

## Citation

> US National Institutes of Health, RePORTER application 10897180, Targeting vulnerabilities in copper metabolism in the development of cancer therapies (5R01CA262664-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897180. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*