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Principal Investigator: Marc Mendillo
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $326,284
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Triple-negative breast cancer (TNBC) refers to a collection of heterogeneous breast tumors that lack expression
of immediately druggable molecules, such as the estrogen and progesterone receptors and human epidermal
growth factor receptor 2. No targeted therapy is currently approved for the vast majority of TNBC patients. TNBC
patients who have received the current standard of care, consisting of chemotherapy, radiation, and surgery,
often experience early tumor recurrence and a significantly worse mortality rate. Therefore, it is critical to identify
and validate clinically viable, life-saving targeted therapies for patients with TNBC. We previously reported that
the oncogenic MYC pathways were activated in ~50% of TNBC cases compared with non-TNBC cases and that
MYC levels were associated with poor outcomes among TNBC patients. Unfortunately, clinical development of
inhibitors that directly target MYC activity has remained challenging. To overcome this challenge, we previously
took an alternative approach known as the synthetic lethal screening approach to identify readily druggable
targets required for MYC-driven tumor viability but that are not essential in non-tumor cells. Our screen identified
the PIM family of kinases, which is composed of the closely related nonessential kinase isoforms PIM1, -2, and
-3 (PIM hereafter), as a promising target in MYC-driven TNBC. We found that PIM expression was elevated in
triple-negative (TN) tumors in clinical samples and was associated with poor patient outcomes. Clinically relevant
pan-PIM inhibitors showed activity in various experimental models of TNBC. However, our single-agent efficacy
studies using preclinical PIM inhibitors showed that although PIM inhibition significantly slowed the growth of TN
tumors, it induced only modest in vivo tumor cell death and regression, suggesting the need for combination
therapies. We have taken robust drug screening approaches and have unexpectedly found that the drug
combination that targets PIM kinases and the proteasome can acutely induce toxic levels of proteotoxic stress
selectively in MYC-overexpressing TNBC cells. Mechanistically, our preliminary observations indicate that PIM
inhibition, which elevates the levels of reactive oxygen species, when combined with proteasome inhibition,
overwhelms the capacity of TNBC cells to continuously degrade damaged proteins, resulting in proteotoxic crisis.
Thus, our observations raise the possibility—and our study will test the hypothesis—that PIM inhibition
represents a unique and clinically viable tool to sensitize TNBC tumors to proteasome inhibition. The successful
execution of this research will allow for the identification and interrogation of clinically exploitable vulnerabilities
in MYC-driven solid-cancer types such as TNBC. The outcomes of this research could also encourage the FDA-
approved proteasome inhibitors (e.g., carfilzomib), which have not been successfully used outside of liquid tumor
types, to be rapidly evaluated in combination with pan-PIM kinase inhibitors in early-stage MYC-driven solid-
tumor trials.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><Abscission><Active Oxygen><Acute><Address><Basal Transcription Factor><Basal transcription factor genes><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Cancer cell line><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Breast tumor cell line><Cancers><Cell Body><Cell Death><Cell Survival><Cell Viability><Cells><Clinical><Clinical Evaluation><Clinical Investigator><Clinical Testing><Collaborations><Collection><Combined Modality Therapy><Death Rate><Disease><Disease Progression><Disorder><Drug Combinations><Drug Screening><Drug Synergism><Drugs><EGF Receptor><EGFR><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Estrogen Receptors><Excision><Experimental Models><Extirpation><FDA approved><Family><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Goals><Growth><HER1><Human><Impairment><In Vitro><Isoforms><Kinases><Life><Liquid substance><Lytotoxicity><Macropain><Macroxyproteinase><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Medication><Modern Man><Multicatalytic Proteinase><Multimodal Therapy><Multimodal Treatment><Multiple Myeloma><Oncogene Products><Oncogene Proteins><Oncogenic><Oncoproteins><Operative Procedures><Operative Surgical Procedures><Outcome><Outcomes Research><Oxidative Stress><Oxygen Radicals><PIM1><PIM1 gene><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pharmaceutical Preparations><Phase><Phosphotransferase Gene><Phosphotransferases><Plasma-Cell Myeloma><Pre-Clinical Model><Preclinical Models><Pro-Oxidants><Progesterone Receptors><Progestin Receptors><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteasome Inhibition><Proteasome Inhibitor><Protein Inhibition><Protein Isoforms><Proteins><Proteosome><Provirus Insertion Site Gene-1><Radiation><Reactive Oxygen Species><Receptor Protein><Recurrent Neoplasm><Recurrent tumor><Removal><Reporting><Research><Resistance><Sampling><Solid><Solid Neoplasm><Solid Tumor><Stress><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><TGF-alpha Receptor><TNBC><Testing><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Growth Factor alpha Receptor><Translating><Transphosphorylases><Tumor Cell><Up-Regulation><Upregulation><Urogastrone Receptor><Validation><Xenograft Model><aberrant folded protein><aberrant folded proteins><abnormal folded protein><abnormal folded proteins><anti-tumor effect><antitumor effect><biological adaptation to stress><breast tumor cell><c-erbB-1><c-erbB-1 Protein><cancer progenitor><cancer progenitor cells><cancer stem cell><cancer sub-types><cancer subtypes><cancer type><chemotherapy><clinical development><clinical relevance><clinical test><clinically relevant><combination therapy><combined modality treatment><combined treatment><cytotoxicity><determine efficacy><drug detection><drug testing><drug/agent><druggable target><early experience><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><evaluate efficacy><examine efficacy><fluid><human model><in vivo><inhibit protein><inhibit proteins><inhibitor><kinase inhibitor><liquid><malignancy><malignant breast tumor><malignant progenitor><malignant stem cell><mammary tumor><misfolded protein><misfolded proteins><model of human><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality rate><mortality ratio><mouse model><multi-modal therapy><multi-modal treatment><multicatalytic endopeptidase complex><murine model><myeloma><myelomatosis><necrocytosis><neoplasm recurrence><neoplasm/cancer><neoplastic cell><novel><ontogeny><overexpress><overexpression><oxidative damage><oxidative injury><pathway><patient oriented outcomes><pim kinase><pre-clinical><preclinical><progenitor-like cell><protein inhibitions><proteotoxic><proteotoxic protein><proteotoxicity><proteotoxin><proto-oncogene protein c-erbB-1><proto-oncogene protein pim><rational design><reaction; crisis><receptor><research clinical testing><resection><resistance mechanism><resistance to therapy><resistant><resistant mechanism><resistant to therapy><screening><screenings><small molecular inhibitor><small molecule inhibitor><standard of care><stem-like cell><stress response><stress; reaction><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><tool><transcription factor><treatment resistance><treatment strategy><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor growth><tumor xenograft><validations><xenograft transplant model><xenotransplant model>