Targeting breast cancer stem cells

 描述（由申请人提供）：肿瘤细胞异质性对开发有效的癌症治疗剂提出了巨大的挑战。除了突变和克隆选择导致的遗传异质性，越来越多的证据表明表观遗传异质性在介导治疗耐药性中起着重要作用。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。在这些层次的顶端是癌症干细胞（CSC），其驱动肿瘤生长和转移。CSC具有表型可塑性，使其能够在间充质和上皮样状态之间转变，这是由肿瘤微环境调节的过程。CSC还表现出对细胞毒性剂和放射疗法的内在抗性，并且还可能对针对大量肿瘤群体的分子靶向疗法具有抗性。CSC的异质性、可塑性和治疗抗性对开发有效的癌症疗法具有深远的意义。 在过去的十年中，我们的实验室已经确定了乳腺癌中CSC的标志物，以及其他肿瘤类型，并开发了体外和小鼠模型，促进了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途径，这些途径调节这些细胞，促进CSC靶向药物的开发，其中一些现已进入临床试验。我们建议通过应用单细胞基因组学和蛋白质组学技术以单细胞分辨率表征CSC异质性来扩展这些研究。我们将开发新的技术，以捕获和分子询问循环CSC在分子注释的PDX模型，以及在主要的患者血液样本。这些技术将有助于更精确地选择靶向CSC的药物，并有助于对CTC靶向临床试验中的患者进行真实的疗效评估。成功靶向CSC有可能显著改善乳腺癌患者以及其他恶性肿瘤患者的结局。

 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.