Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies

Dusp4 在乳腺癌中的作用：肿瘤抑制生物学和治疗策略

基本信息

批准号：
8765222
负责人：
Justin M Balko
金额：
$ 12.46万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8765222
关键词：
Ablation Address Affect Apoptosis Apoptotic Automobile Driving Bioinformatics Biological Biology Breast Breast Cancer Cell Breast Cancer Treatment Cancer Patient Cell Line Cells Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Trials Cytotoxic Chemotherapy Data Dependence Development Diagnosis Doxorubicin Drug Targeting Drug resistance ERBB2 gene Educational workshop Epigenetic Process Estrogen Receptors Experimental Models Faculty Feedback Frequencies Future Gene Expression Profile Gene Targeting Genes Genetic Genetically Engineered Mouse Genome Genomics Goals Health Human Human Resources Institution Knowledge Learning Libraries MAP Kinase Gene MAPK3 gene MAPK8 gene MEKs Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Mentors Methods Methylation Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Molecular Target Outcome Pathway interactions Patients Phase Phenotype Phosphoric Monoester Hydrolases Population Positioning Attribute Publishing Records Regulation Research Research Personnel Resistance Resources Role Signal Pathway Signal Transduction Small Interfering RNA Specificity Structure Testing Therapeutic Therapeutic Agents Training Training Support Training and Education Tumor Suppressor Genes Tumor Suppressor Proteins Universities Woman Work Xenograft Model Xenograft procedure anticancer research base biological research cancer stem cell cancer therapy career career development chemotherapeutic agent chemotherapy clinically relevant docetaxel improved in vivo Model inhibitor/antagonist lectures malignant breast neoplasm mouse model neoplastic cell new therapeutic target novel promoter restoration screening skills therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): The goals of this Pathway to Independence Career Development Proposal are to request support for training to develop expertise in experimental models of breast cancer while addressing a fundamental gap in knowledge that could have a significant impact on the treatment of breast cancer patients. K99/R00 support during this transitional phase of my career will be integral to my successful development as an independent investigator at a top-tier research institution. The training plan outlined herein will take advantage of the extensive resources available at Vanderbilt University as well as key senior personnel with track records of scientific excellence to serve as mentors and collaborators. As part of my pathway to independence I have assembled a mentoring team at Vanderbilt to provide career development advice and scientific direction. Didactic seminars, lectures, and workshops provided by Vanderbilt and the Biological Research Education and Training (BRET) office will provide structured support for this guidance and will help further prepare me for an independent faculty position. A technical workshop offered by Jackson Labs on the Experimental Models of Human Cancer as well as two workshops in Bioinformatics will be taken during the earlier phase of this proposal in order to enhance scientific and technical knowledge on genetically engineered mouse models and to expand my expertise and skills in Bioinformatics, both major features of the work outlined herein. The scientific portion of this proposal focuses on experimentally and mechanistically testing the potential role of DUSP4 as a mediator of drug resistance in breast cancer. DUSP4 is a dual-specificity phosphatase with activity against ERK1/2 and JNK1/2, key signaling components of the MAPK pathways. We have previously shown that DUSP4 loss, in part by epigenetic silencing, is common in basal-like and luminal B breast cancer, and contributes to resistance to chemotherapy-induced apoptosis. Our own published data and the preliminary data in this application support a role for DUSP4 as a mediator of drug resistance in breast cancer, and suggest that genetic or epigenetic DUSP4 loss may be a therapeutically exploitable molecular alteration within the tumor cell. Therefore, in line with these data I will explore two overarching scientific aims; 1) to determine the mechanism by which DUSP4 loss inhibits chemotherapy-induced apoptosis and how this can be circumvented, and 2) to use high-throughput siRNA screening for >7,500 gene targets in isogenic cell lines which lack or express DUSP4 in order to identify synthetic lethal targets in breast cancers with DUSP4 loss. The completion of the scientific aims of this proposal will develop my research skills in experimental models of breast cancer while also developing the rationale for clinical trials to overcome therapeutic resistance in DUSP4-deficient breast cancer. Finally, this proposal seeks identify novel therapeutic targets which could impact breast cancer treatment.

描述（由申请人提供）：本独立之路职业发展提案的目标是请求支持培训，以发展乳腺癌实验模型的专业知识，同时解决可能对乳腺癌治疗产生重大影响的基本知识差距癌症患者。在我职业生涯的这个过渡阶段，K99/R00 支持对于我作为顶级研究机构的独立研究者的成功发展至关重要。本文概述的培训计划将利用范德比尔特大学的广泛资源以及具有卓越科学记录的关键高级人员作为导师和合作者。作为独立之路的一部分，我在范德比尔特组建了一个指导团队，提供职业发展建议和科学方向。范德堡大学和生物研究教育和培训 (BRET) 办公室提供的教学研讨会、讲座和讲习班将为本指导提供结构化支持，并将帮助我进一步为独立教职职位做好准备。杰克逊实验室提供的关于人类癌症实验模型的技术研讨会以及两个生物信息学研讨会将在本提案的早期阶段举行，以增强有关基因工程小鼠模型的科学和技术知识，并扩展我的专业知识和生物信息学技能，这是本文概述的工作的两个主要特征。该提案的科学部分侧重于通过实验和机制测试 DUSP4 作为乳腺癌耐药性介质的潜在作用。 DUSP4 是一种双特异性磷酸酶，具有针对 ERK1/2 和 JNK1/2（MAPK 通路的关键信号传导成分）的活性。我们之前已经表明，DUSP4 缺失（部分是由于表观遗传沉默所致）在基底样乳腺癌和管腔 B 型乳腺癌中很常见，并且有助于抵抗化疗诱导的细胞凋亡。我们自己发表的数据和本申请中的初步数据支持 DUSP4 作为乳腺癌耐药性介质的作用，并表明遗传或表观遗传 DUSP4 丢失可能是肿瘤细胞内治疗上可利用的分子改变。因此，在根据这些数据，我将探索两个总体科学目标； 1) 确定 DUSP4 丢失抑制化疗诱导的细胞凋亡的机制以及如何规避这种机制，以及 2) 使用高通量 siRNA 筛选缺乏或表达 DUSP4 的同基因细胞系中的 >7,500 个基因靶标，以鉴定DUSP4 缺失的乳腺癌合成致死靶点。该提案的科学目标的完成将提高我在乳腺癌实验模型方面的研究技能，同时也为克服 DUSP4 缺陷型乳腺癌的治疗耐药性的临床试验奠定基础。最后，该提案寻求确定可能影响乳腺癌治疗的新治疗靶点。