Research Project 2: Targetin Tumor-Initiating Cell (TIC) Heterogeneity To Overcome Chemotherapy Resistance

研究项目2：靶向肿瘤起始细胞（TIC）异质性以克服化疗耐药性

• 批准号: 10681678
• 负责人: Michael T. Lewis
• 金额: $ 22.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681678
• 关键词: Aftercare; Behavior Therapy; Binding; Biological Assay; Breast Cancer therapy; CD44 gene; Carboplatin; Cell physiology; Cell surface; Cells; Chemoresistance; Clinical Trials; Collection; Coupled; DNA sequencing; Data; Epithelial; Erinaceidae; FDA approved; Fatty acid glycerol esters; Gene Expression; Genes; Heterogeneity; Human; Impairment; Individual; Laboratories; Lead; Light; Mammospheres; Mediating; Mesenchymal; Microfluidics; Modeling; Molecular; Natural regeneration; Pathway interactions; Pattern; Physiological; Population; Process; Proteins; Proteome; Radio; Regulator Genes; Regulatory Pathway; Reporter; Reporter Genes; Research Project Grants; Resistance; STAT3 gene; Signal Pathway; Signal Transduction; Site; Systemic Therapy; Testing; Transplantation; Tumor-Derived; Visualization; Work; activity marker; aldehyde dehydrogenase 1; base; cancer stem cell; cell type; chemoradiation; chemotherapy; comparative; exome; in vivo; mRNA Expression; mammary; metabolome; neoplastic cell; notch protein; novel; patient derived xenograft model; precision medicine; predicting response; prevent; protein expression; response; single-cell RNA sequencing; targeted agent; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; treatment effect; treatment response; triple-negative invasive breast carcinoma; tumor

PROJECT SUMMARY We and others have shown that a subset of tumor cells capable of regenerating new tumors, termed variously as tumor-initiating cells (TIC) or “cancer stem cells” (CSC), are comparatively resistant to current systemic chemo- and radio-therapies relative to the bulk of the tumor. As such, the guiding premise for our work over the past decade, is that therapeutic targeting of processes required for survival or function of TIC will allow elimination of such cells at both the primary and metastatic sites, thereby enhancing response to current systemic therapies. However, it has become clear from several laboratories using current cell surface markers, enzymatic activity markers, and lentiviral signaling reporters for Wnt, Hedgehog, and STAT3-mediated signaling, that TIC are heterogeneous not only across tumors, but also show different behaviors, treatment responses, and reporter gene expression at the primary and metastatic sites within a given tumor model. Thus, it is critical to understand the diversity of TIC types both within and across tumors, as well as to understand how such cells differ in function between the primary and metastatic site, in order to target them effectively – particularly in “triple-negative” breast cancer (TNBC), for which there are no approved targeted therapies. We hypothesize that there exist molecularly distinct classes of TIC in TNBC. As a consequence, differential responses to individual chemotherapies depend, in part, on the class(es) of TIC present in a given tumor. If true, we further assert that identifying and targeting class-specific TIC functions may help overcome chemotherapy resistance. In order to identify candidate regulatory genes or pathways functioning in a spectrum of PDX-derived TIC isolated from primary and metastatic sites, we propose to determine first whether TIC derived from either the primary or metastatic site show identical, or different, patterns of activation of signaling networks implicated in TIC function using lentiviral fluorescent reporters specific for signaling pathways and transcription factors implicated in TIC function. We will then identify candidate molecular mechanisms required for TIC activity at the population and single cell levels using RNAseq. In order to determine whether in vivo targeting of TIC-related genes/pathways can augment response to carboplatin, and lead to elimination of different classes of TIC at both the primary and metastatic sites, we will evaluate the ability of FDA-approved agents targeting TIC to augment treatment response alone or in combination with carboplatin at the primary and metastatic sites, and assay the effect of treatment on TIC function in vivo. Results may be used to guide planning and execution of human clinical trials and inform precision medicine efforts.

项目摘要 我们和其他人表明，一部分能够再生新肿瘤的肿瘤细胞，称为各种各样的肿瘤 作为肿瘤发射细胞（TIC）或“癌症干细胞”（CSC），对电流的全身性具有相对抗性 相对于大部分肿瘤的化学和放射性治疗。因此，我们在我们工作的指导前提 过去的十年是，靶向生存或功能所需的过程的治疗靶向将允许 消除主要和转移性位点的此类细胞，从而增强对电流的反应 系统性疗法。但是，使用当前细胞表面标记的几个实验室已经清楚地清楚了， Wnt，刺猬和STAT3介导的酶活性标记和慢病毒信号记者 信号，该抽动不仅在肿瘤之间是异质的，而且表现出不同的行为，治疗 在给定肿瘤模型中的原发性和转移位点的反应和报告基因表达。那， 了解肿瘤内部和跨肿瘤的抽动类型的多样性以及了解 为了有效地靶向，这些细胞在原发性位点和转移位点之间的功能如何不同 - 特别是在“三阴性”乳腺癌（TNBC）中，没有批准的靶向疗法。 我们假设在TNBC中存在TIC的分子类别。结果，差异 对单个化学疗法的反应部分取决于给定肿瘤中存在的TIC的类别。如果 没错，我们进一步断言，识别和定位特定类的抽动功能可能有助于克服 化学疗法抗性。 为了确定在PDX衍生的TIC中起作用的候选调节基因或途径 我们从原发性和转移性位点分离出来，提议首先确定是否源自 主站点或转移性位点显示了实现的信号网络激活模式 使用针对信号通路和转录因子的慢病毒荧光报告的抽动功能 在TIC功能中实现。然后，我们将确定在TIC活性处所需的候选分子机制 使用RNASEQ的种群和单细胞水平。 为了确定在体内靶向与TIC相关基因/途径是否可以增强对 卡铂，导致在主要和转移性部位消除不同类别的TIC，我们将 评估针对TIC的FDA批准的药物单独增加治疗反应的能力 在原发性和转移性位点与卡铂结合，并测定治疗对TIC的影响 在体内功能。结果可用于指导人类临床试验的计划和执行并告知 精密医学工作。