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：
9887288
负责人：
David D Tran
金额：
$ 52.18万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9887288
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 Epithelium Exposure to FDA approved Failure Fluorouracil Future Genes Genomics Goals Growth Hormones Human 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 Regulator Genes 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 high risk improved inhibiting antibody innovation insight lymph nodes malignant breast neoplasm mouse model neoplastic cell neutralizing monoclonal antibodies novel novel therapeutics 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.

抽象的患有持续性微小残留病的局部浸润性三阴性乳腺癌 (TNBC) 患者（MRD）尽管新辅助治疗仍面临发生致命转移的重大风险。乳腺癌治疗中未满足的突出需求是这种高失败风险的主要原因是罕见的、低水平的存在。增殖性播散性肿瘤细胞 (lpDTC)，许多 lpDTC 可以持续存在。在重新激活形成转移之前，已尝试消除远处器官多年。由于其稀有性，尚未成功，因此很难分离出单个 lpDTC 来确定治疗靶点。为此，我们报告了 IL-6、IL-6 受体和 p38 (IL-6/R/p38) 轴的鉴定和表征，作为在培养的人类中维持绝大多数 lpDTC 所需的关键信号通路。 TNBC 细胞和 TNBC 小鼠模型，骨髓 (BM) 中的 lpDTC 可以通过以下方式被迫脱离静止状态：更重要的是，一旦急性重新激活，lpDTC 就会变得极其敏感。因此，IL-6/R 途径是一个有吸引力的治疗靶点，在本提案中，我们将测试一种新的治疗靶点。在 TNBC 患者的 I 期和 II 期试验中，通过特异性抑制 IL-6/R 通路来强制治疗策略 lpDTCs进入增殖状态，然后使用常规化疗来消除这些细胞。首先，我们将确定。在一项针对 Sarilumab（一种 IL-6R）的标准剂量发现 I 期研究中，这种治疗策略对患者是否安全最近批准用于治疗类风湿性关节炎的抑制性抗体药物，顺序与卡培他滨（卡培他滨）联合使用标准乳腺癌化疗药物，用于转移性乳腺癌患者（目标 1）。目的是确定联合用药的耐受性和安全性以及联合用药的推荐剂量接下来，我们将在患者中使用此推荐剂量方案进行 II 期单臂研究。新辅助治疗后乳腺组织或周围淋巴结持续存在 MRD 的 I-III 期 TNBC 治疗（目标 2）。 II 期的目标是确定该药物组合在清除 BM 方面的效果如何。 lpDTC，如果是的话，清除 BM lpDTC 的患者是否具有更高的两年无进展生存率与历史上单独使用卡培他滨治疗的患者相比，在目标 3 中，我们将从 BM 中分离出个体 lpDTC。本试验中使用传统的基于磁体的富集方法和本地开发的方法收集抽吸物微流控装置 1) 计算治疗前后的 lpDTC，以确定治疗后的 lpDTC 清除效果测试药物组合；2) 对单个 lpDTC、原发性和转移性肿瘤样本进行基因组学分析我们将使用最近开发的新型计算平台来分析基因网络。乳腺癌细胞在转移过程中对治疗和肿瘤微环境的反应发生变化。目标是 1) 更深入地了解 lpDTC 的生成和维护方式，以及 2) 产生额外收益；可以在不久的将来与 IL-6/R 通路结合以改善 DTC 靶向策略的目标。