# Mechanisms Promoting Copper Dependent Cell Death in Cancer

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $648,408

## Abstract

PROJECT SUMMARY
Copper is an essential co-factor for enzymes across the animal kingdom yet even modest intracellular
concentrations can be toxic, resulting in cell death. The toxicity of copper prompted the development of copper
ionophores such as elesclomol as potential cancer therapeutics. However, lack of clarity regarding their
mechanism of action has prevented their clinical development despite a favorable tolerability profile in clinical
trials. We have recently described that copper ionophores promote a surprising new form of regulated cell death,
distinct from other known and well annotated cell death pathways (such as apoptosis, ferroptosis and
necroptosis). This new form of regulated cell death is copper dependent (hence termed “cuproptosis”) and is
regulated by mitochondrial FDX1 and cellular protein lipoylation, a conserved lysine post-translational
modification regulating only 4 key mitochondrial enzymes. Despite this essential role in enabling cuproptosis,
little is known about the natural function of FDX1 in the cell, and the regulation and manifestation of protein
lipoylation in different cancer types. Establishing a coherent mechanism explaining FDX1 and protein lipoylation
regulation of copper ionophore induced cell death is crucial for any future attempts to repurpose these molecules
as cancer therapeutics. As such, we will combine multidisciplinary approaches that include genomic and
proteomic perturbation strategies with metabolite profiling and multiplexed imaging in cell culture and distinct
mouse tumor models to determine the natural function of the key regulators of cuproptosis (FDX1 and protein
lipoylation) in cancer cell growth and tumor formation, enabling a mechanistic understanding of how they regulate
cuproptosis. Specifically, in Aim 1, we will focus on elucidating the natural function of the key regulator of
cuproptosis, FDX1, in cells. We will take a focused approach to determine if it regulates Fe-S cluster biosynthesis
or protein lipoylation, we will use proteomic approaches to characterize its protein-protein interactions, and we
will perform deep mutational scanning to map the structure-function interactions of FDX1. In Aim 2, we will
specifically focus on the unique regulatory role of lipoylated DLAT in promoting cuproptosis. We will use different
image-based approaches to define the biophysical properties of lip-DLAT aggregates and their protein
composition identifying links to multiple other cellular features. In Aim 3 we will first explore the levels of protein
lipoylation across hundreds of cancer cell lines and establish the cell state associated with high lipoylation cancer
cells. Then, we will determine the manifestation and dependency on FDX1 and protein lipoylation in both classic
xenograft tumor models and in models of metastatic tumors growing in different organs. Lastly, we will use these
in vivo models to establish the efficacy and on-target engagement of copper ionophores in cancer cell models
...

## Key facts

- **NIH application ID:** 11093599
- **Project number:** 7R01CA279550-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Sandro Santagata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,408
- **Award type:** 7
- **Project period:** 2023-07-08 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11093599

## Citation

> US National Institutes of Health, RePORTER application 11093599, Mechanisms Promoting Copper Dependent Cell Death in Cancer (7R01CA279550-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11093599. Licensed CC0.

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