Functional Characterization of HER Family Variant Biology and Resistance in Cancer

项目总结/摘要 博士Tikvah Hayes是达纳法伯大学Matthew Meyerson博士实验室的博士后研究员 癌症研究所和布罗德研究所。她的长期职业目标是降低癌症相关死亡率， 通过确定癌症发展的机制和确定有吸引力的治疗策略， 更好的病人护理。为了实现这一目标，Hayes博士独特地利用了功能基因组学， 分子生物学方法来回答与癌症生物学相关的基本问题。 人表皮生长因子受体（HER）家族的受体酪氨酸激酶（RTK）经常被改变， 在癌症中。对患者肿瘤的靶向组测序揭示了两种肿瘤中的许多激活性改变， EGFR和HER 2。因此，几代分子靶向EGFR和HER 2疗法 已设计并已证明对某些EGFR或HER 2突变型癌症患者有效。 然而，患者观察到的HER家族变异的一个子集缺乏报告的功能持续存在，并且在缺乏的情况下， 函数数据的变量被归类为未知重要性的变量。目前尚不清楚是否所有EGFR和 HER 2错义突变是致癌驱动因子，对临床EGFR或HER 2靶向治疗敏感。 该提案旨在从功能和机制上表征EGFR和HER 2错义的作用， 在促进肿瘤发生和对酪氨酸激酶抑制剂（TKI）疗法的抗性中的变体。目标1将寻求 为携带罕见EGFR突变且无临床批准EGFR的患者提名替代策略- 存在靶向治疗。目的2将评价罕见EGFR变体的致癌能力。最后，在目标3中， 将询问HER 2变体致癌能力和TKI敏感性。这项研究将大大 提高我们对RTK错义变体如何促进癌症发展和对 靶向治疗。 博士Hayes将学习新技术，包括类器官培养，体内细胞系异种移植，胸腔内移植， 肺注射、肿瘤成像和组织处理/染色，同时提高她的职业生涯 通过赠款写作、科学传播和领导力方面的培训来促进发展。在K99阶段， 博士海耶斯的研究和培训将在马修·迈耶森博士的主要指导下进行， 癌症基因组学的领导者，并将通过与高水平专家的合作来补充， 通量遗传筛选、临床基因组学、结构生物学和体内小鼠建模，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.