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Investigating Rational Combination Therapies for Triple-Negative Breast Cancer

研究三阴性乳腺癌的合理联合疗法

基本信息

批准号：
10367060
负责人：
Dai Horiuchi
金额：
$ 34.35万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367060
关键词：
Acute Address Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cell Death Cell Survival Cells Chemotherapy and/or radiation Clinical Clinical Investigator Collaborations Collection Combined Modality Therapy Disease Disease Progression Drug Combinations Drug Screening Drug Synergism Epidermal Growth Factor Receptor Estrogen Receptors Excision Experimental Models FDA approved Family Goals Growth Human Impairment In Vitro Life Liquid substance Malignant Neoplasms Mammary Neoplasms Multiple Myeloma Oncogenic Oncoproteins Operative Surgical Procedures Outcome Outcomes Research Oxidative Stress PIM1 gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phosphotransferases Pre-Clinical Model Progesterone Receptors Proteasome Inhibition Proteasome Inhibitor Protein Isoforms Proteins Reactive Oxygen Species Recurrence Reporting Research Resistance Sampling Savings Solid Solid Neoplasm Stress Testing Translating Up-Regulation Validation Xenograft Model antitumor effect base biological adaptation to stress cancer stem cell cancer subtypes cancer type clinical development clinically relevant cytotoxicity drug testing druggable target early experience efficacy evaluation efficacy study human model in vivo inhibitor kinase inhibitor malignant breast neoplasm misfolded protein molecular targeted therapies mortality mouse model multicatalytic endopeptidase complex neoplastic cell novel overexpression oxidative damage pre-clinical proteotoxicity proto-oncogene protein pim rational design receptor research clinical testing resistance mechanism screening small molecule inhibitor standard of care stem-like cell targeted treatment therapy resistant tool transcription factor treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft

项目摘要

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.

项目总结/文摘