Targeting breast cancer stem cells

靶向乳腺癌干细胞

• 批准号: 8955932
• 负责人: MAX S. WICHA
• 金额: $ 93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955932
• 关键词: Blood; Blood specimen; Cell Count; Cells; Clinical Trials; Cytotoxic agent; Development; Drug Targeting; Epigenetic Process; Epithelial; Genetic Heterogeneity; Genomics; Heterogeneity; In Vitro; Laboratories; Malignant Neoplasms; Mediating; Mesenchymal; Methodology; Modeling; Mutation; Neoplasm Metastasis; Pathway interactions; Patients; Population; Process; Property; Proteomics; Radiation therapy; Resistance; Resolution; Role; Stem cells; Technology; Therapeutic; Time; Treatment Efficacy; cancer stem cell; cancer therapy; cytotoxic radiation; improved outcome; malignant breast neoplasm; mouse model; new technology; novel; public health relevance; targeted treatment; therapy resistant; tumor; tumor growth; tumor microenvironment

 DESCRIPTION (provided by applicant): Tumor cellular heterogeneity presents a formidable challenge to the development of effective cancer therapeutics. In addition to well-studied genetic heterogeneity resulting from mutation and clonal selection, there is mounting evidence for a fundamental role of epigenetic heterogeneity in mediating therapeutic resistance. Epigenetic mechanisms regulating cellular differentiation generate hierarchically organized cellular clones within tumors. At the apex of these hierarchies are cancer stem cells (CSCs) which drive tumor growth and metastasis. CSCs are endowed with phenotypic plasticity enabling them to transition between mesenchymal and epithelial-like states, processes regulated by the tumor microenvironment. CSCs also display intrinsic resistance to cytotoxic agents and radiation therapy and also may be resistant to molecularly targeted therapies aimed at bulk tumor populations. CSC heterogeneity, plasticity, and therapeutic resistance have profound implications for development of effective cancer therapies. Over the past decade, our laboratory has identified markers for CSCs in breast cancer, as well as other tumor types and developed in vitro and mouse models that have facilitated isolation and characterization of these cells. We have identified a number of cell intrinsic and microenvironmentally driven pathways that regulate these cells facilitating development of CSC-targeting drugs, a number of which have now entered clinical trials. We propose to extend these studies by applying single-cell genomic and proteomic technologies to characterize CSC heterogeneity at single-cell resolution. We will develop novel technologies to capture and molecularly interrogate circulating CSCs in molecularly annotated PDX models, as well as in primary patient blood samples. These technologies will facilitate more precise selection of agents to target CSCs, as well as facilitating real time assessment of therapeutic efficacy for patients on CTC targeting clinical trials. The successful targeting of CSCs has the potential to significantly improve the outcomes of patients with breast cancer, as well as other malignancies.

 描述（由申请人提供）：肿瘤细胞异质性对有效癌症治疗的开发提出了巨大的挑战，除了经过充分研究的突变和克隆选择导致的遗传异质性之外，越来越多的证据表明表观遗传异质性在介导中发挥着重要作用。调节细胞分化的表观遗传机制在肿瘤内产生分层组织的细胞克隆，位于这些分层结构顶端的是癌症干细胞（CSC），它们驱动肿瘤生长和分化。 CSCs 具有表型可塑性，使其能够在间充质状态和上皮样状态之间转变，受肿瘤微环境调节的过程也表现出对细胞毒性药物和放射治疗的内在抵抗力，并且还可能对针对批量的分子靶向治疗产生抵抗力。 CSC 的异质性、可塑性和治疗耐药性对有效癌症疗法的开发具有深远的影响。 在过去的十年中，我们的实验室已经确定了乳腺癌以及其他肿瘤类型中 CSC 的标志物，并开发了体外和小鼠模型，这些模型有助于这些细胞的分离和表征。我们已经确定了许多细胞内在和微环境驱动的细胞。调节这些细胞的途径促进 CSC 靶向药物的开发，其中一些药物现已进入临床试验，我们将通过应用单细胞基因组和蛋白质组技术来扩展这些研究，以单细胞分辨率表征 CSC 异质性。开发新技术在分子注释的 PDX 模型以及主要患者血液样本中捕获和分子询问循环 CSC，这些技术将有助于更精确地选择针对 CSC 的药物，并促进针对临床 CTC 患者的治疗效果的实时评估。试验中，CSC 的成功靶向有可能显着改善乳腺癌以及其他恶性肿瘤患者的预后。