Functional Characterization of HER Family Variant Biology and Resistance in Cancer

项目摘要/摘要 Tikvah Hayes博士是达纳-法伯大学Matthew Meyerson博士实验室的博士后研究员 癌症研究所和博德研究所。她的长期职业目标是降低癌症相关死亡率和 通过确定癌症发展的机制和确定有吸引力的治疗策略而遭受痛苦 为了更好地照顾病人。为了实现这一目标，海斯博士独特地利用了功能基因组学和 分子生物学方法回答与癌症生物学有关的基本问题。 人类表皮生长因子受体(HER)家族的受体酪氨酸激酶(RTK)经常发生改变 在癌症中。对患者肿瘤的靶向小组测序显示了这两种肿瘤中的一些激活变化 EGFR和HER2。因此，几代分子靶向的EGFR和HER2疗法 已经被设计并被证明对一些患有EGFR或HER2突变癌症的患者有效。 然而，患者观察到的缺乏报告功能的家族变种的子集仍然存在，并且在缺乏的情况下 的功能数据被归类为意义未知的变种。目前尚不清楚是否所有的EGFR和 HER2错义突变是致癌因素，对临床EGFR或HER2靶向治疗敏感。 这项建议旨在从功能和机制上表征EGFR和HER2错义的作用 促进肿瘤发生和对酪氨酸激酶抑制剂(TKI)治疗耐药的变异。目标1将寻求 为携带罕见的EGFR突变的患者提名替代策略，这些患者没有临床批准的EGFR- 靶向治疗是存在的。目的2将评估罕见的EGFR变异体的致癌能力。最后，在目标3中， HER2变异体致癌能力和TKI敏感性将被询问。拟议中的研究将极大地 提高我们对RTK错义变异如何促进癌症发生和抵抗的理解 有针对性的治疗。 海斯博士将学习新的技术，包括器官培养，体内细胞系异种移植，胸腔内 肺部注射、肿瘤成像和组织处理/染色，同时促进了她的事业 通过赠款撰写、科学交流和领导力方面的培训实现发展。在K99阶段， 海斯博士的研究和培训将在马修·迈耶森博士的主要指导下进行，他是一名 癌症基因组学领域的领先者，并将与高技术领域的专家合作进行补充。 吞吐量基因筛查、临床基因组学、结构生物学、活体小鼠建模以及 顾问委员会由Michael Eck博士、William Hahn博士、Pasi Janne博士和Carla Kim博士组成。

Project Summary/Abstract Dr. Tikvah Hayes is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and the Broad Institute. Her long-term career goal is to reduce cancer-associated mortality and suffering by determining the mechanisms of cancer development and identifying attractive therapeutic strategies for better patient care. To accomplish this goal, Dr. Hayes uniquely leverages both functional genomics and molecular biology methods to answer fundamental questions related to cancer biology. The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTK) is frequently altered in cancer. Targeted panel sequencing of patient tumors has revealed a number of activating alterations in both EGFR and HER2. As a consequence, several generations of molecularly targeted EGFR and HER2 therapies have been designed and have proved efficacious for some patients with either EGFR- or HER2-mutant cancers. However, a subset of patient-observed HER family variants lacking a reported function persist and in the absence of functional data are classified as variants of unknown significance. It remains unknown whether all EGFR and HER2 missense mutations are oncogenic drivers and are sensitive to clinical EGFR or HER2-targeted therapies. This proposal aims to functionally and mechanistically characterize the role of EGFR and HER2 missense variants in promoting oncogenesis and resistance to tyrosine kinase inhibitor (TKI) therapies. Aim 1 will seek to nominate alternative strategies for patients harboring rare EGFR mutations where no clinically approved EGFR- targeted therapy exists. Aim 2 will evaluate the oncogenic capacity of rare EGFR variants. Finally, in Aim 3, HER2 variant oncogenic capacity and TKI sensitivity will be interrogated. The proposed research will greatly improve our understanding of how RTK missense variants promote cancer development and resistance to targeted therapies. Dr. Hayes will learn new techniques which will include organoid culturing, in vivo cell line xenografts, intrathoracic lung injections, tumor imaging and tissue processing/staining, while simultaneously enhancing her career development through training in grant-writing, science communication, and leadership. During the K99 phase, Dr. Hayes’ research and training will be carried out under the primary mentorship of Dr. Matthew Meyerson, a leader in cancer genomics, and will be additionally complemented by collaborations with experts in high- throughput genetic screening, clinical genomics, structural biology, and in vivo mouse modeling, as well as mentoring from an advisory committee consisting of Drs. Michael Eck, William Hahn, Pasi Janne, and Carla Kim.