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.

抽象的局部侵入性三重阴性乳腺癌（TNBC）的患者持续存在最小残留疾病（MRD）尽管新辅助治疗仍具有发生致命转移的重大风险。这代表了在乳腺癌治疗方面的未满足需求。这种高失败风险的主要原因是存在罕见，低 - 增殖的散布肿瘤细胞（LPDTC），对治疗具有高度抗性。许多LPDTC可以持续遥远的器官多年，然后重新激活形成转移。尝试消除TNBC中LPDTC的尝试具有由于其稀有性而没有成功，因此很难隔离单个LPDTC来识别治疗靶标。到那一端，我们报告了IL-6，IL-6受体和p38（IL-6/R/p38）轴的识别和表征为A 维持TNBC中大部分LPDTC所需的临界信号通路。在文化的人类中 TNBC细胞和TNBC的小鼠模型，骨髓中的LPDTC（BM）可以简单地被迫静止不动。抑制IL-6/R信号传导。更重要的是，一旦急性重新激活，LPDTC就会对化学疗法。这是IL-6/R途径是一个有吸引力的治疗靶标。在此提案中，我们将测试一本小说 TNBC患者的I期和II期试验中的治疗策略，通过特别抑制IL-6/R途径 LPDTC进入增殖，然后使用常规化学疗法消除这些细胞。首先，我们将确定在标准剂量发现的萨里卢马布（Sarilumab）I阶段研究中，这种治疗策略是否安全抑制最近批准用于治疗类风湿关节炎的抗体药物，依次与Capecitabine合并在转移性乳腺癌患者中，标准乳腺癌化学疗法药物（AIM 1）。第一阶段目的是确定组合的耐受性和安全性以及组合的建议剂量对于II期。接下来，我们将使用此建议的剂量方案进行II期单臂研究与新辅助后的乳腺组织或周围淋巴结中有持续的MRD的I-III期TNBC 治疗（目标2）。 II期目标是确定该药物组合清除BM的有效性 LPDTC，如果是这样与仅用卡捷他滨治疗的患者相比。在AIM 3中，我们将将单个LPDTC与BM分离使用常规磁铁的富集方法在本试验中收集的抽吸物和本地开发的微流体设备至1）在处理前后列举LPDTC，以确定LPDTC清除效率测试药物组合； 2）对单个LPDTC进行基因组学分析，原发性和转移性肿瘤样品来自同一患者。我们将使用最近开发的新型计算平台来分析基因网络对治疗和肿瘤微环境的响应变化，这些环境使乳腺癌细胞转移期间过渡。目标是1）更深入地了解如何生成和维护LPDTC； 2）产生额外可以在不久的将来与IL-6/R途径相结合的目标。