Investigating the role of the small GTPase RIT1 in lung adenocarcinoma

 描述(申请人提供)：爱丽丝·伯杰博士是达纳-法伯癌症研究所和布罗德研究所马修·迈耶森博士实验室的博士后研究员。她的长期职业目标，与NCI的使命一致，是通过确定癌症发展机制和确定有吸引力的治疗目标来减少与癌症相关的死亡率和痛苦。为了实现这一目标，伯杰博士独一无二地利用基因组学和细胞生物学方法来回答与癌症生物学相关的基本问题。最近，伯杰博士在肺腺癌中发现了小GTP酶基因RIT1的体细胞突变。肺腺癌是男性和女性中最常见、最致命的癌症类型之一。这项拟议的研究将测试RIT1突变是否是肿瘤启动和/或维持所必需的，并将确定肺上皮细胞中RIT1功能的关键影响因素。第一个目的是通过建立一种肺特异的、可诱导的RIT1突变小鼠模型来检验RIT1是肺腺癌启动事件的假设。为了确定RIT1的作用机制，第二个目标将利用无偏倚的定量蛋白质组学和表达谱分析来确定肺上皮细胞中与RIT1相互作用或受RIT1调控的蛋白质/基因。第三个目标将使用shRNA和CRISPR在易处理的细胞模型中介导的功能丧失遗传实验来确定RIT1突变细胞的遗传依赖性。总之，这些研究将确定RIT1本身或其任何下游效应物是否代表肺腺癌治疗开发的有希望的靶点。该奖项的指导阶段将包括体内和细胞模型的建立和分析，同时申请者通过专注的生物统计学和领导力培训来促进她的职业发展。在独立阶段，候选RIT1效应器将在体外和体内进行验证，结果将用于申请继续独立资助。伯杰博士拥有的优秀研究环境和设施包括达纳-法伯癌症研究所和布罗德研究所的实验室空间和全面的机构准入。伯杰博士的研究和培训将通过与老鼠病理学、老鼠建模和蛋白质组学方面的知名专家的合作以及由包括威廉·哈恩博士、托德·戈卢布博士、彼得·哈默曼博士和爱德华·哈洛博士在内的领先癌症生物学家组成的咨询委员会的指导而得到进一步加强。

 DESCRIPTION (provided by applicant): Dr. Alice Berger is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at Dana-Farber Cancer Institute and the Broad Institute. Her long-term career goal, in alignment with the mission of the NCI, is to reduce cancer-associated mortality and suffering by determining mechanisms of cancer development and identifying attractive therapeutic targets. To accomplish this goal, Dr. Berger uniquely leverages both genomics and cell biological methods to answer fundamental questions relating to cancer biology. Recently, Dr. Berger identified somatic mutations in the small GTPase gene, RIT1, in lung adenocarcinoma, one of the most prevalent and deadly cancer types in both men and women. The proposed research will test whether RIT1 mutations are required for tumor initiation and/or maintenance and will determine the critical effectors of RIT1 function in lung epithelial cells. The first aim will test the hypothesis that RIT1 is an initiating event in lung adenocarcinoma by generating a lung-specific, inducible mouse model of RIT1 mutation. To determine the mechanism of action of RIT1, the second aim will utilize unbiased quantitative proteomics and expression profiling to identify proteins/genes interacting with or regulated by RIT1 in lung epithelial cells. The third aim will determine genetic dependencies of RIT1-mutant cells using shRNA and CRISPR-mediated loss- of-function genetic experiments in tractable cellular models. Together, these studies will determine if RIT1 itself or any of its downstream effectors represent promising targets for therapeutic development in lung adenocarcinoma. The mentored phase of this award will involve establishment and analysis of in vivo and cellular models while the applicant simultaneously enhances her career development through focused biostatistics and leadership training. During the independent phase, candidate RIT1 effectors will be validated in vitro and in vivo, and the results used to apply for continued independent funding. The outstanding research environment and facilities available to Dr. Berger include laboratory space and full institutional access at both Dana-Farber Cancer Institute and the Broad Institute. Dr. Berger's research and training will be additionally enhanced by collaborations with established experts in mouse pathology, mouse modeling, and proteomics, as well as by mentoring from an advisory committee of leading cancer biologists including Dr. William Hahn, Dr. Todd Golub, Dr. Peter Hammerman, and Dr. Edward Harlow.