Functional Characterization of HER Family Variant Biology and Resistance in Cancer

HER 家族变异生物学的功能特征和癌症抵抗力

基本信息

批准号：
10746883
负责人：
Tikvah K Hayes
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746883
关键词：
Acceleration Activities of Daily Living Advisory Committees Biological Assay Biology Bypass Cancer Biology Cancer Model Cancer Patient Cell Line Cell Proliferation Cell Survival Chimeric Proteins Classification Clinical Collaborations Communication Complement Dana-Farber Cancer Institute Data Dependence Development Dimerization ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Family Generations Genes Genetic Screening Genomics Goals Grant Heterodimerization Homo Human Immunofluorescence Immunologic In Vitro Injections Investigation Laboratories Leadership Learning Lung Malignant Neoplasms Malignant neoplasm of lung Mentors Mentorship Methods Missense Mutation Modeling Molecular Biology Molecular Target Mutagenesis Mutate Mutation Nude Mice Oncogenes Oncogenic Organoids Patient Care Patients Phase Point Mutation Postdoctoral Fellow Receptor Protein-Tyrosine Kinases Relapse Reporting Research Resistance Role STAT1 gene Science Signal Transduction Stains Techniques Therapeutic Training Tyrosine Kinase Inhibitor Validation Variant Writing Xenograft procedure cancer genomics cancer imaging career career development clinical investigation design functional genomics genetic approach image processing improved in vivo in vivo Model inhibitor inhibitor therapy lapatinib member mortality mouse model mutant novel therapeutic intervention patient subsets pharmacologic pre-clinical receptor resistance mutation structural biology targeted treatment tissue processing tumor tumor growth tumor initiation tumor xenograft tumorigenesis variant of unknown significance

项目摘要

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.

项目摘要/摘要 Tikvah Hayes博士是Dana-Farber的Matthew Meyerson博士实验室的博士后研究员癌症研究所和广泛研究所。她的长期职业目标是降低与癌症相关的死亡率和通过确定癌症发展的机制并确定有吸引力的治疗策略来遭受苦难为了更好的患者护理。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（她）的受体酪氨酸激酶（RTK）家族经常被改变在癌症中。患者肿瘤的靶向面板测序揭示了两者的许多激活改变 EGFR和HER2。结果，几代人靶向EGFR和HER2疗法对某些EGFR或HER2突变癌患者的设计并已被证明并有效。但是，一部分患者观察的她的家庭变体缺乏报告的功能，并且在没有的情况下功能数据的归类为未知重要性的变体。是否所有EGFR和 HER2错义突变是致癌驱动因素，对临床EGFR或HER2靶向疗法敏感。该建议旨在在功能和机械上表征EGFR和HER2错过的角色促进对酪氨酸激酶抑制剂（TKI）疗法的肿瘤发生和抗性的变体。 AIM 1将寻求为具有罕见的EGFR突变的患者提名替代策略，而没有临床认可的EGFR- 存在靶向疗法。 AIM 2将评估稀有EGFR变体的致癌能力。最后，在AIM 3中 HER2变体致癌能力和TKI敏感性将受到质疑。拟议的研究将大大提高我们对RTK错义变体如何促进癌症发展和抵抗力的理解靶向疗法。 Hayes博士将学习新技术，其中包括器官培养，体内细胞系异种移植，静脉曲制肺注射，肿瘤成像和组织加工/染色，同时增强她的职业生涯通过培训，科学沟通和领导才能发展。在K99阶段， Hayes博士的研究和培训将以Matthew Meyerson博士的主要心态进行癌症基因组学领导者，并将通过与高级专家合作完成吞吐量遗传筛查，临床基因组学，结构生物学和体内小鼠建模以及由DRS组成的咨询委员会的指导。迈克尔·埃克（Michael Eck），威廉·哈恩（William Hahn），帕西·詹妮（Pasi Janne）和卡拉·金（Carla Kim）。