Jo Ishizawa, MD, PhD

University of Texas MD Anderson Cancer Center

Titles + affiliations

Assistant Professor, Department of Leukemia, Division of Cancer Medicine
University of Texas MD Anderson Cancer Center

Research

Targeting Mitochondrial Anti-Lipid Peroxidation to Induce Ferroptosis in Therapy Resistant AML

Summary

Acute myeloid leukemia (AML) is a rapidly progressive blood cancer, the 5-year overall survival being up to 30%. Particularly relapsed cases show only 10-15% of one-year overall survival. Despite a number of promising molecularly targeted agents, the majority of patients still relapse, underlining the urgent unmet need in AML therapeutics. To overcome the therapy-resistance, we here propose a novel therapeutic concept by investigating a mode of cancer cell death termed "ferroptosis". Our preliminary data suggest that inducing ferroptosis, by targeting one of the key regulatory protein GPX4, overcomes therapy-resistance in AML cells. Moreover, we also found that ferroptosis induced in AML cells have uniqueness in that the cell death mechanisms largely rely on the intracellular organelle mitochondria. This is not only a novel scientific finding, but also provides an opportunity to optimize our concept of ferroptosis-based therapy. Specifically, we found that combining drugs targeting specific proteins in the mitochondria enhances AML cell death caused by GPX4 inhibition. Based on the preliminary data, we propose to combine two novel investigational drugs to target GPX4 and mitochondria, and one FDA-approved drug venetoclax (VEN). VEN is a recently approved and highly promising drug for AML therapy, but acquired resistance is a clinical challenge. Having potential to overcome VEN-resistance too, our project will provide the preclinical rationale of ferroptosis-based therapy.

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Leukemia Research Foundation grant
$100K awarded in 2022

Disease focus
Acute myeloid leukemia (AML)

Research focus
Treatment (targeted therapy)