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Novel Methods of Chemo-sensitizing Low-proliferative Disseminated Tumor Cells in Triple Negative Breast Cancer

三阴性乳腺癌中低增殖性播散性肿瘤细胞化疗增敏的新方法

基本信息

批准号：
10407055
负责人：
David D Tran
金额：
$ 55.77万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407055
关键词：
Acute Adjuvant Adoption Aftercare Animal Model Animals Aspirate substance BRCA1 gene BRCA2 gene Bone Marrow Bone Marrow Cells Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast Oncology Breast cancer metastasis Bromodeoxyuridine Cancer Etiology Cell model Cells Cessation of life Chemosensitization Chemotherapy-Oncologic Procedure Critical Pathways Cytokine Network Pathway Cytotoxic agent Data Disease Distant Dose Drug Combinations Epigenetic Process Epithelial Exposure to FDA approved Failure Fluorouracil Future Genomics Goals Growth Hormones Human IL-6 inhibitor In complete remission Individual Interleukin 6 Receptor Interleukin-1 Interleukin-6 Lead Magnetism Maintenance Malignant Neoplasms Mammary Gland Parenchyma Mesenchymal Metabolic Clearance Rate Metastatic breast cancer Methods Microfluidic Microchips Monoclonal Antibodies Nature Neoadjuvant Therapy Neoplasm Circulating Cells Neoplasm Metastasis Oral Organ Pathologic Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phase Phase I/II Clinical Trial Phase I/II Trial Phenotype Positioning Attribute Primary Neoplasm Process Prodrugs Progression-Free Survivals Regimen Reporting Research Personnel Residual Neoplasm Resistance Rheumatoid Arthritis Risk Role Safety Sampling Signal Pathway Signal Transduction Site Source Surrogate Markers Survival Rate System TACSTD1 gene Techniques Testing Therapeutic Toxic effect Treatment Failure Up-Regulation Woman arm autocrine base cancer subtypes capecitabine chemosensitizing agent chemotherapy computational platform driver mutation efficacy testing epithelial to mesenchymal transition experience gene network gene regulatory network high risk improved inhibiting antibody innovation insight lymph nodes malignant breast neoplasm mouse model neoplastic cell neutralizing monoclonal antibodies novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase paracrine phase 1 study pre-clinical receptor spatiotemporal stem therapeutic target therapy resistant transcriptome treatment response treatment strategy triple-negative invasive breast carcinoma tumor microenvironment

项目摘要

ABSTRACT Patients with locally invasive triple negative breast cancer (TNBC) who have persistent minimal residual disease (MRD) despite neoadjuvant therapy are at significant risks of developing lethal metastasis. This represents one of the outstanding unmet needs in breast cancer therapy. A major cause of this high failure risk is the presence of rare, low- proliferative disseminated tumor cells (lpDTCs), which are highly resistant to treatment. Many lpDTCs can persist in distant organs for many years before reactivating to form metastasis. Attempts at eliminating lpDTCs in TNBC have not been successful due to their rarity, making it difficult to isolate individual lpDTCs to identify therapeutic targets. To that end, we report the identification and characterization of the IL-6, IL-6 receptor, and p38 (IL-6/R/p38) axis as a critical signaling pathway required for the maintenance of a significant majority of lpDTCs in TNBC. In cultured human TNBC cells and mouse models of TNBC, lpDTCs in the bone marrow (BM) can be forced out of quiescence simply by inhibiting IL-6/R signaling. More importantly, once acutely reactivated, lpDTCs become exquisitely sensitive to chemotherapy. Thus, the IL-6/R pathway is an attractive therapeutic target. In this proposal, we will test a novel therapeutic strategy in a Phase I and II trial in patients with TNBC by specifically inhibiting the IL-6/R pathway to force lpDTCs into proliferation, and then use conventional chemotherapy to eliminate these cells. First, we will determine whether this treatment strategy is safe in patients in a standard dose finding Phase I study of sarilumab, an IL-6R inhibiting antibody drug recently approved to treat rheumatoid arthritis, sequentially combined with capecitabine, a standard breast cancer chemotherapy drug, in patients with metastatic breast cancer (Aim 1). The Phase I’s objectives are to determine tolerability and safety of the combination and the recommended dose of the combination for the Phase II. Next, we will conduct a Phase II single-arm study using this recommended dose regimen in patients with stage I-III TNBC who have persistent MRD in breast tissue or surrounding lymph nodes after neoadjuvant therapy (Aim 2). The Phase II objectives are to determine how effective this drug combination is at clearing BM lpDTCs, and if so whether patients cleared of BM lpDTCs have a higher rate of progression-free survival at two years compared to patients historically treated with capecitabine alone. In Aim 3, we will isolate individual lpDTCs from BM aspirates collected in this trial using the conventional magnet-based enrichment method and a locally developed microfluidic device to 1) enumerate lpDTCs before and after treatment to determine the lpDTC clearing efficacy of the test drug combination; and 2) to perform genomics analysis of single lpDTCs, primary and metastatic tumor samples from the same patients. We will use a novel computational platform recently developed to analyze gene network changes in response to treatment and tumor microenvironments that breast cancer cells transition during metastasis. The goals are to 1) gain a deeper understanding of how lpDTCs are generated and maintained; and 2) yield additional targets that can be combined with the IL-6/R pathway to improve DTC-targeting strategies in the near future.

摘要