BACH2 in Melanoma Development and Resistance

BACH2 在黑色素瘤发展和抵抗中的作用

• 批准号: 8949027
• 负责人: Florian Karreth
• 金额: $ 17.73万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-09 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949027
• 关键词: Accounting; Advisory Committees; American Cancer Society; Antioxidants; Automobile Driving; Award; B-Lymphocytes; BACH2 gene; BCL6 gene; BRAF gene; Biological; Biomedical Research; Cancer Biology; Cancer Etiology; Cells; Cessation of life; Core Facility; Development; Diagnosis; Disease Progression; Drug Metabolic Detoxication; Drug Targeting; Drug resistance; Educational workshop; Environment; Evaluation; Event; FDA approved; Faculty; Gene Targeting; Genes; Genetic Screening; Genomics; Goals; Health; Human; In Vitro; Laboratories; Light; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Metabolism; Metastatic Melanoma; Molecular; Molecular Genetics; Mus; Mutation; Nevus; Oncogenic; Outcome; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Program Development; Proteins; Research Personnel; Research Proposals; Research Support; Resistance; Resistance development; Role; Scientist; Series; Signal Pathway; Signal Transduction; Skin Cancer; Sleeping Beauty; Structure of germinal center of lymph node; TP53 gene; Training; Training Programs; Tumor Suppressor Proteins; Unresectable; Up-Regulation; Validation; Work; anticancer research; base; career; career development; combinatorial; experience; in vivo; inhibitor/antagonist; lectures; leukemia/lymphoma; medical schools; melanocyte; melanoma; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; p19ARF; plasma cell differentiation; programs; research study; response; small molecule inhibitor; symposium; targeted treatment; tool; transcription factor; treatment strategy; tumor; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): This research proposal, prepared by Dr. Florian Karreth, describes a three-year training program for the development of an academic career in cancer research. Dr. Karreth has several years of experience in mouse modeling and cancer biology and has recently begun to study the role of BACH2 in melanoma progression and drug resistance in Dr. Lewis Cantley's laboratory. He identified BACH2 in two independent forward genetic screens that were aimed at discovering mutations that either accelerate oncogenic BRAF-driven melanoma development or confer resistance of melanoma to the BRAFV600E-specific small molecule inhibitor vemurafenib. Dr. Karreth now proposes a detailed molecular and cell biological characterization of BACH2. BACH2 is a transcription factor that has mainly been studied in B-cells where it regulates germinal center formation and plasma cell differentiation. Genomic deletion of BACH2 is observed in a considerable portion of leukemias and lymphomas, suggesting a tumor suppressive role. Dr. Karreth proposes to characterize the effect of BACH2 loss on oncogenic transformation of murine and human melanocytes and melanoma cells. Moreover, Dr. Karreth will utilize novel tools to study the effect of BACH2 loss on tumor progression in a BRAFV600E-driven mouse model of melanoma. BACH2 regulates the expression or activity of proteins that play central roles in cancer such as p19ARF, p53, and the master regulator of the antioxidant program, NRF2. The contribution of these factors and other BACH2 targets to the tumor suppressive function of BACH2 will be studied. Moreover, Dr. Karreth will examine how BACH2 confers resistance of BRAFV600E-driven melanoma to vemurafenib in vitro and in vivo. To this end, he will analyze NRF2-regulated drug detoxification upon loss of BACH2 and investigate whether other NRF2-depedent and -independent transcriptional targets are involved. These analyses will shed light on the tumor suppressive function of BACH2 in melanoma and provide novel approaches for therapy. Evaluation of such approaches will be a focus of Dr. Karreth's future research. Prior to the Award, Dr. Karreth will receive further training at Weill Cornell Medical College (WCMC) in the laboratory of Dr. Lewis Cantley, a renowned expert in signaling and metabolism. Dr. Cantley's laboratory will provide Dr. Karreth with the opportunity to gain additional expertise to become a well-rounded scientist. Dr. Karreth will benefit from WCMC's stimulating environment that is created by close interactions with outstanding faculty and by multiple core facilities that provide excellent research support. Dr. Karreth is committed to a career in biomedical research and has outlined a comprehensive Career Development program to achieve his goal of independence. This program includes lectures and seminar series, scientific conferences, and educational workshops and courses at WCMC. In addition, the guidance and advice from Dr. Karreth's advisory committee and his collaborators - all experts in their respective fields - will greatly facilitate his transition to an independent investigator position.

 描述(由申请人提供)：这份研究建议书由弗洛里安·卡雷思博士准备，描述了一项为期三年的培训计划，旨在发展癌症研究的学术生涯。卡雷思博士在小鼠建模和癌症生物学方面有多年经验，最近开始在刘易斯·坎特利博士的实验室研究BACH2在黑色素瘤进展和耐药性中的作用。他在两个独立的正向基因筛查中发现了BACH2，这两个筛查旨在发现加速致癌的BRAF驱动的黑色素瘤发展或使黑色素瘤对BRAFV600E特异性小分子抑制剂Vemurafenib产生耐药性的突变。Karreth博士现在提出了BACH2的详细分子和细胞生物学特征。Bach2是一种主要在B细胞中研究的转录因子，它调节生发中心的形成和浆细胞的分化。在相当一部分白血病和淋巴瘤中观察到BACH2的基因组缺失，这表明BACH2具有肿瘤抑制作用。Karreth博士建议对BACH2缺失对小鼠、人类黑素细胞和黑色素瘤细胞的致癌转化的影响进行表征。此外，Karreth博士将利用新的工具在BRAFV600E驱动的黑色素瘤小鼠模型中研究BACH2缺失对肿瘤进展的影响。Bach2调节在癌症中起核心作用的蛋白质的表达或活性，如p19ARF、P53和抗氧化剂计划的主要调节因子NRF2。这些因素和其他BACH2靶点对BACH2的肿瘤抑制作用的贡献将被研究。此外，Karreth博士将在体外和体内研究BACH2是如何使BRAFV600E驱动的黑色素瘤对维莫拉非尼产生耐药性的。为此，他将分析BACH2缺失时NRF2调控的药物解毒作用，并调查是否涉及其他NRF2依赖和独立的转录靶标。这些分析将阐明BACH2在黑色素瘤中的肿瘤抑制功能，并为治疗提供新的方法。对这些方法的评估将是卡雷思博士未来研究的重点。在获奖之前，Karreth博士将在威尔康奈尔医学院(WCMC)的刘易斯·坎特利博士的实验室接受进一步的培训，刘易斯·坎特利博士是一位著名的信号和新陈代谢专家。坎特利博士的实验室将为卡雷思博士提供机会，让他获得更多的专业知识，成为一名全面发展的科学家。Karreth博士将受益于WCMC的激励环境，这种环境是通过与优秀教师的密切互动以及提供出色研究支持的多个核心设施创造的。Karreth博士致力于生物医学研究，并概述了一项全面的职业发展计划，以实现他的独立目标。该计划包括WCMC的讲座和研讨会系列、科学会议、教育研讨会和课程。此外，Karreth博士的顾问委员会和他的合作者--他们都是各自领域的专家--的指导和建议将极大地促进他向独立调查员职位的过渡。