# Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $338,743

## Abstract

Malignant melanoma causes the majority of skin cancer-related deaths in the United
States representing a public health burden of considerable magnitude. Our recent
research has identified artemisinins, an important class of redox-antimalarials in clinical
use worldwide, as redox-directed anticancer agents that target disruption of cellular iron
homeostasis, a common alteration of premalignant and malignant cells that causes
hypersensitivity to cytotoxic oxidative stress. In this R01 application entitled
'Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention', we
test the hypothesis that oncogene-driven dysregulation of iron homeostasis represents a
molecular Achilles heel characteristic of melanomagenesis that can be targeted by
artemisinin-endoperoxide antimalarials. In this comprehensive project, we also test
feasibility of using artemisinin-based combination therapeutics (ACT), FDA-approved for
pharmacotherapeutic anti-malaria intervention, targeting malignant melanoma in relevant
disease models: aim #1: First, the mechanistic relationship between dysregulated c-
MYC and transferrin receptor expression, iron homeostasis, and cellular hypersensitivity
to artemisinin-based redox intervention will be examined in cell culture and human
premalignant and tumor tissue interrogated in microarray format. Novel molecular
targets modulated through covalent adduction after iron-dependent artemisinin activation
will be identified based on proteomic experimentation using a fluorescently labeled
artemisinin probe followed by in vivo efficacy testing in a spontaneous murine genetic
melanoma model. aim #2: Following our prior studies on antimelanoma activity of the
autophagy-directed ACT antimalarial amodiaquine, we explore mechanism and
feasibility of amodiaquine-based experimental chemotherapeutic intervention targeting
early and late melanomagenesis. aim #3:Finally, we will test the hypothesis that
artemisinin-based intervention combined with specific autophagy-directed ACT
antimalarials (amodiaquine, piperaquine, lumefantrine) provides improved therapeutic
efficacy inhibiting tumor growth and overcoming BRAF-inhibitor resistance in preclinical
xenograft models. The proposed research guides the rational design of future
preclinical/clinical studies that promise to facilitate repurposing of FDA-approved ACT-
antimalarials for anti-melanoma intervention, benefitting patients in the very near future.

## Key facts

- **NIH application ID:** 9858313
- **Project number:** 5R01CA229418-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Georg T Wondrak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,743
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858313

## Citation

> US National Institutes of Health, RePORTER application 9858313, Repurposing Clinical ACT Antimalarials for Experimental Melanoma Intervention (5R01CA229418-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858313. Licensed CC0.

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