Targeting breast cancer stem cells

靶向乳腺癌干细胞

• 批准号: 10331012
• 负责人: MAX S. WICHA
• 金额: $ 91.14万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331012
• 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.

 描述（由适用提供）：肿瘤细胞异质性对有效癌症治疗的发展提出了巨大的挑战。除了突变和克隆选择引起的良好研究的遗传异质性外，还有越来越多的证据表明表观遗传异质性在介导治疗抗性中起着基本作用。表观遗传机制调节细胞分化会在肿瘤内产生分层组织的细胞克隆。这些层次结构的顶点是癌症干细胞（CSC），促进肿瘤生长和转移。 CSC具有表型可塑性，从而使它们能够在间质和上皮状状态之间过渡，即受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耐药性，并且可能对针对大量肿瘤群体的分子靶向疗法有抵抗力。 CSC异质性，可塑性和治疗性抗性对有效癌症疗法的发展具有深远的影响。 在过去的十年中，我们的实验室已经确定了乳腺癌中CSC的标记，以及其他肿瘤类型，并在体外和小鼠模型中开发了这些细胞的分离和表征。我们已经确定了许多细胞固有和微环境驱动的途径，这些途径调节了这些细胞发展CSC靶向药物的发育，其中许多现在已经进入了临床试验。我们建议通过应用单细胞基因组和蛋白质组学技术来表征单细胞分辨率的CSC异质性来扩展这些研究。我们将开发新的技术，以捕获和分子询问分子注释的PDX模型以及原发性患者血液样本中的循环CSC。这些技术将促进针对CSC的药物的更精确选择，并促进针对临床试验的CTC患者的治疗效率的实时评估。成功靶向CSC有可能显着改善乳腺癌患者以及其他Malignancys的结局。

项目成果

HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells.

• DOI: 10.1016/j.chembiol.2021.02.013
• 发表时间: 2021-05-20
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Xia L;Wen L;Qin Y;Dobson HE;Zhang T;Comer FI;Hinrichs MJ;Oberst MD;Coats SR;Chang AE;Liu Y;Bao Y;Dai F;Wicha MS;Li Q
• 通讯作者: Li Q

Inhibition of FAK kinase activity preferentially targets cancer stem cells.

• DOI: 10.18632/oncotarget.18517
• 发表时间: 2017-08-01
• 期刊: Oncotarget
• 作者: Kolev VN;Tam WF;Wright QG;McDermott SP;Vidal CM;Shapiro IM;Xu Q;Wicha MS;Pachter JA;Weaver DT
• 通讯作者: Weaver DT

Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells.

基于树突状细胞的免疫疗法在 CD105 人肾癌干细胞中激发有效的抗肿瘤免疫反应

• DOI: 10.1002/mc.22697
• 发表时间: 2017
• 期刊: Mol Carcinog
• 作者: Zhang Xiao-Fei;Weng De-Sheng;Pan Ke;Zhou Zi-Qi;Pan Qiu-Zhong;Zhao Jing-Jing;Tang Yan;Jiang Shan-Shan;Chen Chang-Long;Li Yong-Qiang;Zhang Hong-Xia;Chang Alfred E;Wicha Max S;Zeng Yi-Xin;Li Qiao;Xia Jian-Chuan
• 通讯作者: Xia Jian-Chuan

The Roles of the Let-7 Family of MicroRNAs in the Regulation of Cancer Stemness.

• DOI: 10.3390/cells10092415
• 发表时间: 2021-09-14
• 期刊: Cells
• 影响因子: 6
• 作者: Ma Y;Shen N;Wicha MS;Luo M
• 通讯作者: Luo M

The pleiotropic effects of TNFα in breast cancer subtypes is regulated by TNFAIP3/A20.

• DOI: 10.1038/s41388-018-0472-0
• 发表时间: 2019-01
• 期刊: Oncogene
• 影响因子: 8
• 作者: Lee E;Ouzounova M;Piranlioglu R;Ma MT;Guzel M;Marasco D;Chadli A;Gestwicki JE;Cowell JK;Wicha MS;Hassan KA;Korkaya H
• 通讯作者: Korkaya H