BACH2 in Melanoma Development and Resistance

BACH2 在黑色素瘤发展和抵抗中的作用

• 批准号: 9329377
• 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/9329377
• 关键词: 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; Genetic Transcription; Genomics; Goals; Human; In Vitro; Laboratories; Light; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Metabolism; Metastatic Melanoma; Molecular; Molecular Genetics; Molecular Target; 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; 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; experimental study; in vivo; in vivo Model; inhibitor/antagonist; lectures; leukemia/lymphoma; medical schools; melanocyte; melanoma; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; p19ARF; plasma cell differentiation; programs; public health relevance; 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）：这项研究计划由 Florian Karreth 博士准备，描述了一项为期三年的癌症研究学术生涯发​​展培训计划。 Karreth 博士在小鼠建模和癌症生物学方面拥有多年经验，最近开始在 Lewis Cantley 博士的实验室研究 BACH2 在黑色素瘤进展和耐药性中的作用。他在两次独立的正向遗传筛选中发现了 BACH2，这些筛选的目的是发现加速致癌 BRAF 驱动的黑色素瘤发展或赋予黑色素瘤对 BRAFV600E 特异性小分子抑制剂维莫非尼 (vemurafenib) 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 是一种转录因子，主要在 B 细胞中进行研究，它调节生发中心形成和浆细胞分化。在相当一部分白血病和淋巴瘤中观察到 BACH2 的基因组缺失，表明其具有肿瘤抑制作用。 Karreth 博士提议描述 BACH2 缺失对小鼠和人类黑色素细胞和黑色素瘤细胞致癌转化的影响。此外，Karreth 博士将利用新工具在 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 调节在癌症中发挥核心作用的蛋白质的表达或活性，例如 p19ARF、p53 以及抗氧化程序的主调节因子 NRF2。将研究这些因素和其他 BACH2 靶点对 BACH2 肿瘤抑制功能的贡献。此外，Karreth 博士将研究 BACH2 如何在体外和体内赋予 BRAFV600E 驱动的黑色素瘤对维莫非尼的耐药性。为此，他将分析 BACH2 丢失后 NRF2 调节的药物解毒，并研究是否涉及其他依赖 NRF2 和不依赖 NRF2 的转录靶点。这些分析将揭示 BACH2 在黑色素瘤中的肿瘤抑制功能，并提供新的治疗方法。对此类方法的评估将是 Karreth 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) 的信号和代谢领域著名专家 Lewis Cantley 博士的实验室中接受进一步培训。 Cantley 博士的实验室将为 Karreth 博士提供获得额外专业知识的机会，从而成为一名全面发展的科学家。 Karreth 博士将受益于 WCMC 的激励性环境，该环境是通过与优秀教师的密切互动以及提供卓越研究支持的多个核心设施而创建的。 Karreth 博士致力于生物医学研究事业，并制定了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、科学会议以及教育研讨会和课程。此外，Karreth 博士的顾问委员会和他的合作者（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研究者职位的过渡。