Targeting breast cancer stem cells

靶向乳腺癌干细胞

• 批准号: 10093979
• 负责人: MAX S. WICHA
• 金额: $ 91.55万
• 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/10093979
• 关键词: Blood; Blood specimen; Cells; Clinical Trials; Cytotoxic agent; Development; Drug Targeting; Epigenetic Process; Epithelial; Genetic Heterogeneity; Genetic study; Genomics; Heterogeneity; In Vitro; Laboratories; Malignant Neoplasms; Mediating; Mesenchymal; Methodology; Molecular; Mutation; Neoplasm Metastasis; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Population; Process; Property; Proteomics; Radiation therapy; Resistance; Resolution; Role; Technology; Therapeutic; Time; Treatment Efficacy; cancer biomarkers; cancer stem cell; cancer therapy; cytotoxic radiation; improved outcome; malignant breast neoplasm; molecular targeted therapies; mouse model; new technology; novel; patient derived xenograft model; public health relevance; stem cells; 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.