Targeting Metabolic Vulnerabilities of Triple Negative Breast Cancer Stem Cells

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: MAX S. WICHA
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $474,547
Funding agency: National Cancer Institute

PROJECT SUMMARY/ABSTRACT
Triple negative breast cancer (TNBC) is the most aggressive subtype with increased propensity for metastasis
and few treatment options. Mounting evidence suggests that cancer stem-like cells (CSCs) in TNBC contribute
to the early recurrence and poor clinical outcomes. Thus, identification of novel therapeutic approaches
effectively targeting CSCs is crucial for improving outcome in TNBC. We propose to target CSCs in TNBC by
exploiting their overexpression of two redox regulating enzymes, NQO1 and SOD1 as a therapeutic vulnerability.
Utilizing a potent NQO1-bioactivatable redox cycling compound, IB-DNQ, which generates large amounts of
reactive oxygen species in CSCs via futile redox cycling, we propose to examine the feasibility of utilizing IB-
DNQ alone, or in combination with SOD1 inhibition, to effectively target CSCs across the EMT-MET CSC state
continuum. We will address three specific aims: 1) To demonstrate the efficacy of IB-DNQ alone or in
combination with SOD1 inhibition in targeting CSCs in vitro and in mouse models of human TNBC; 2) To
determine the mechanisms of cell death induced by IB-DNQ based pro-oxidant strategies; and 3) To determine
how IB-DNQ based pro-oxidant strategies modulate antitumor immunity in immunocompetent mouse models.
This proposal will evaluate a novel pro-oxidant-based approach in selectively targeting CSCs in TNBC and
elucidate the mechanism of action for futile oxidant generators in activating mitochondrial apoptotic and
pyroptotic cell death with resultant stimulation of antitumor immunity. As NQO1 and SOD1 are overexpressed
in many solid tumors, this therapeutic strategy may have wide applicability.

Terms: <ALDH><Active Oxygen><Adjuvant><Antioxidants><Apopain><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 3><Apoptotic><Breast Cancer><CASP-3><CASP3><CASP3 gene><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><Cancer Treatment><Cancers><Cell Body><Cell Death><Cell Death Induction><Cell Protection><Cells><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Cytoprotection><Dehydrogenases><Disease><Disorder><Enzyme Gene><Enzymes><Epithelium><Generations><Genetic><H2O2><Heterograft><Heterologous Transplantation><Hydrogen Peroxide><Hydroperoxide><IPO-B><Immune><Immune Targeting><Immune mediated therapy><Immunes><Immunochemical Immunologic><Immunocompetent><Immunodeficient Mouse><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><Impairment><In Vitro><Indophenol Oxidase B><MNSOD><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Manganese Superoxide Dismutase><Mediating><Membrane Potentials><Mesenchymal><Metabolic><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Mitochondria><Mitochondrial Superoxide Dismutase><Mn Superoxide Dismutase><Mn-SOD><Molecular><Murine><Mus><Neoplasm Metastasis><Outcome><Oxidants><Oxidation-Reduction><Oxidizing Agents><Oxidoreductase><Oxidoreductase Gene><Oxygen Radicals><PARP Cleavage Protease><PARP Cleavage Protease Gene><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Pro-Oxidants><Process><Production><Programmed Cell Death><Quinone Compound><Quinones><Reactive Oxygen Species><Recurrence><Recurrent><Redox><Reductases><Resistance><Resting Potentials><SCA-1><SCA-1 Gene><SOD-1><SOD-1 protein><SOD1><SOD1 gene><SOD1 gene product><SOD2><SOD2 gene><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><Secondary Neoplasm><Secondary Tumor><Solid Neoplasm><Solid Tumor><Superoxide Anion><Superoxide Dismutase 2><Superoxide Radical><Superoxides><Supporting Cell><TNBC><Therapeutic><Transmembrane Potentials><Tumor Cell><Tumor Immunity><Work><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><Yama><Yama protein><aldehyde dehydrogenases><anti-cancer therapy><anti-tumor immunity><antitumor immunity><cancer cell><cancer immunity><cancer metastasis><cancer microenvironment><cancer progenitor><cancer progenitor cells><cancer stem cell><cancer therapy><cancer-directed therapy><caspase-3><catalase><cell killing><cell type><check point blocker><checkpoint blockers><chemo/radiation therapy><chemotherapy and radiotherapy><conventional therapy><conventional treatment><cysteine protease P32><cytoprotective><electron acceptor><female outcomes><human model><immune check point blocker><immune checkpoint blockers><immune competent><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><immunological status><improved><improved outcome><malignancy><malignant breast tumor><malignant progenitor><malignant stem cell><metabolic profile><mitochondrial><mitochondrial membrane><model of human><mouse model><murine model><necrocytosis><neoplasm/cancer><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><outcomes among females><outcomes among women><outcomes in females><outcomes in women><overexpress><overexpression><oxidant stress><oxidation reduction reaction><oxidative damage><oxidative injury><patient oriented outcomes><pharmacologic><progenitor-like cell><radiation or chemotherapy><resistance to therapy><resistant><resistant to therapy><stem-like cell><superoxide dismutase 1><synergism><therapeutic resistance><therapy resistant><treatment resistance><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><women's outcomes><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>