BACH2 in Melanoma Development and Resistance

 描述（由申请人提供）：本研究计划由Florian Karreth博士编写，描述了一个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有多年的经验，最近在刘易斯Cantley博士的实验室开始研究BACH 2在黑色素瘤进展和耐药性中的作用。他在两个独立的正向遗传筛选中鉴定了BACH2，这些筛选旨在发现加速致癌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vemurafenib耐药性的突变。Karreth博士现在提出了BACH 2的详细分子和细胞生物学表征。BACH2是一种转录因子，主要在B细胞中研究，它调节生发中心的形成和浆细胞分化。在相当一部分白血病和淋巴瘤中观察到BACH 2的基因组缺失，表明其具有肿瘤抑制作用。Karreth博士建议表征BACH 2缺失对鼠和人黑素细胞和黑色素瘤细胞的致癌转化的影响。此外，Karreth博士将利用新的工具来研究BACH 2缺失对BRAFV 600 E驱动的黑色素瘤小鼠模型中肿瘤进展的影响。BACH2调节在癌症中发挥核心作用的蛋白质的表达或活性，如p19ARF，p53和抗氧化程序的主要调节因子NRF2。将研究这些因子和其他BACH 2靶点对BACH 2肿瘤抑制功能的贡献。此外，Karreth博士将研究BACH 2如何在体外和体内赋予BRAFV 600 E驱动的黑色素瘤对维罗非尼的耐药性。为此，他将分析BACH2丧失后NRF2调节的药物解毒作用，并研究是否涉及其他NRF2依赖性和非依赖性转录靶点。这些分析将揭示BACH 2在黑色素瘤中的肿瘤抑制功能，并提供新的治疗方法。对这些方法的评估将是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）的刘易斯坎特利博士的实验室接受进一步的培训，他是信号和代谢方面的著名专家。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，使其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，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的职业生涯，并概述了一个全面的职业发展计划，以实现他的独立目标。该计划包括讲座和研讨会系列，科学会议，以及WCMC的教育研讨会和课程。此外，Karreth博士的咨询委员会及其合作者（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。

 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.