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Principal Investigator: Michelle M Martinez
Organization: UNIVERSIDAD CENTRAL DEL CARIBE
Fiscal Year: 2024
Award: $117,029
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Triple Negative Breast Cancer (TNBC) is an aggressive and lethal breast cancer subtype more commonly
diagnosed on younger (<40y) women of color (Hispanics and African American), who are more likely to have
disease recurrence and who have an overall shorter survival. Furthermore, additional limitations (i.e. drug
toxicity, and therapy resistance) persist in the clinic for TNBC patients. Thus, a critical need exists to discover
more desirable targeted therapeutic modalities that selectively target TNBC tumor cells while leaving normal
cells unaffected, enhancing a complete response and reducing TNBC-associated mortality rates. Accordingly,
our goal is to reduce BC mortality by identifying unique vulnerabilities of TNBC that can be exploited through the
development of selective therapeutic agents. We recently identified the natural product ergosterol peroxide a
steroidal compound found in fungi, as a potent antiproliferative agent against TNBC cell models with little to no
effect on noncancerous cells. We demonstrated that EP is more potent towards TNBC than HER2-positive
models. EP induces ROS and apoptosis in TNBC cells and reduces tumor volume in TNBC models in vivo.
However, EP’s mode of action (MOA) remains to be defined. Extended periods of oxidative stress in the
mitochondria lead to accumulation of damaged proteins, which are normally removed by ubiquitination via the
VCP/ANKZF1 pathway. We have synthesized EP in gram scale and show that EP accumulates in the cytosol
and affects VCP and ANKZF1 interactions, raising the possibility that the VCP/ANKZF1 complex is targeted
during its assembly prior to arriving to the mitochondria. Thus, taking advantage of TNBC’s dependency on sterol
uptake, removal of misfolded proteins and altered redox homeostasis, we propose that EP serves as a
VCP/ANKZF1 complex protein-protein inhibitor (PPI). We hypothesize that EP targets the VCP/ANKZF1
complex, impairing the ability of cancer cells to clear damaged proteins and causing mitochondria dysfunction to
induce TNBC cell death. To test the hypothesis we will identify the mechanism by which EP targets the
VCP/ANKZF1 complex in TNBC models using biophysical assays and synthesized EP-probes (Aim 1). The
results from this Aim will validate that targeting VCP/ANKZF1 complex induces increases misfolded and
aggregated proteins, which lead to cancer cell death. We will determine the efficacy of EP using syngeneic
models injected with doxycycline inducible ANKZF1 silenced cells, and in TNBC PDXs. EP safety and bio-
availability will also be determined and studied by MTD and PK/PD (Aim 2). The result of this aim will provide
data needed for the next step towards the translational development of EP. Student participation in this
hypothesis-driven research will improve the pipeline for URM students in biomedical research and lead to
improved BC treatment.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><4T1><ANK Domain><ANK Repeat><APF-1><ATP-Dependent Proteolysis Factor 1><Abscission><Address><Affect><African American><Afro American><Afroamerican><Aminoacyl-tRNA hydrolase><Ankyrin Repeat><Ankyrin Repeat Domain><Apoptosis><Apoptosis Pathway><Assay><Autoregulation><Bioassay><Bioavailability><Biological><Biological Assay><Biological Availability><Biomedical Research><Biophysics><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Patient><Breast Cancer Treatment><Breast PDX models><Breast Tumor Patient><Breast tumor model><CRISPR><CRISPR/Cas system><Cancers><Cell Body><Cell Death><Cell Death Induction><Cell Line><Cell model><CellLine><Cells><Cellular Assay><Cellular model><Cessation of life><Chemicals><Cholesterol><Cholesterol Homeostasis><Clinic><Clinical Research><Clinical Study><Closure by Ligation><Clustered Regularly Interspaced Short Palindromic Repeats><Complex><Cytosol><Data><Death><Death Rate><Dependence><Development><Diagnosis><Disease><Disorder><Dose><Doxycycline><Drug toxicity><ERBB2><ERBB2 gene><Early Diagnosis><Environment><Enzyme Gene><Enzymes><Ergosterol><Excision><Extirpation><Extravasation><Female><Future><Genes><Goals><HER -2><HER-2><HER2><HER2 Genes><HER2/neu><HMG-20><Heterograft><Heterologous Transplantation><High Mobility Protein 20><Hispanic Americans><Homeostasis><Impairment><In complete remission><Knowledge><Lead><Leakage><Ligation><MCF-10A><MCF10A><MCF10A cells><Macropain><Macroxyproteinase><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Membrane><Mice><Mice Mammals><Mitochondria><Mitochondrial Proteins><Modality><Modeling><Multicatalytic Proteinase><Murine><Mus><NEU Oncogene><NEU protein><Natural Products><Normal Cell><Normal Tissue><Normal tissue morphology><Oncogene ErbB2><Oxidation-Reduction><Oxidative Stress><PK/PD><Pathway interactions><Patient-derived xenograft models of breast cancer><Patients><Pb element><Peroxides><Physiologic Availability><Physiological Homeostasis><Prognosis><Programmed Cell Death><Property><Prosome><Protac><Proteasome><Proteasome Endopeptidase Complex><Proteins><Proteolysis targeting chimeric><Proteosome><Puerto Rico><Recurrent disease><Redox><Relapsed Disease><Removal><Research><Resistance><Safety><Scientist><Spillage><Sterols><Strains Cell Lines><Structure><Students><Substrate Specificity><Surgical Removal><Survival Rate><System><TKR1><TNBC><Testing><Therapeutic><Therapeutic Agents><Toxic effect><Toxicities><Tumor Cell><Tumor Volume><URM student><Ubiquitilation><Ubiquitin><Ubiquitination><Ubiquitinoylation><United States><VCP/p97><Vibramycin><Woman><Xenograft><Xenograft procedure><Xenotransplantation><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><aberrant folded protein><aberrant folded proteins><abnormal folded protein><abnormal folded proteins><aggressive breast cancer><alpha-6-Deoxyoxytetracycline><anti-cancer therapeutic><anti-proliferative agents><antiproliferative agents><biologic><biophysical foundation><biophysical principles><biophysical sciences><breast cancer PDX><breast cancer patient-derived xenograft><breast tumor cell><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer progression><cancer sub-types><cancer subtypes><cell assay><chemotherapy><cholesterol metabolism><clinical relevance><clinically relevant><cofactor><complete response><cultured cell line><determine efficacy><developmental><early detection><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><erbB-2 Genes><evaluate efficacy><examine efficacy><fungus><heavy metal Pb><heavy metal lead><herstatin><improved><in vivo><in vivo Model><inhibitor><insoluble aggregate><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><membrane structure><misfolded protein><misfolded proteins><mitochondrial><mitochondrial dysfunction><mortality><mortality rate><mortality ratio><mouse model><multicatalytic endopeptidase complex><murine model><naturally occurring product><necrocytosis><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neu Genes><novel><oxidation reduction reaction><p97-VCP protein><pathway><peptidyl-tRNA hydrolase><pharmacokinetics and pharmacodynamics><pharmacologic><pre-clinical><preclinical><protein aggregate><protein aggregation><protein complex><proteolysis targeting chimera><proteotoxic protein><proteotoxin><public health relevance><resection><resistant><stem><student engagement><student motivation><student participation><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor progression><ubiquination><ubiquitin conjugation><underrepresented minority student><uptake><valosin containing protein p97><valosin-containing protein><valosine-containing protein><women of color><xeno-transplant><xeno-transplantation>