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.

项目概要/摘要 Tikvah Hayes 博士是丹纳—法伯癌症研究所 Matthew Meyerson 博士实验室的博士后研究员她的长期职业目标是降低癌症相关死亡率和癌症研究所。通过确定癌症发展机制并确定有吸引力的治疗策略来了解癌症的痛苦为了更好地护理患者，Hayes 博士独特地利用了功能基因组学和分子生物学方法来回答与癌症生物学相关的基本问题。受体酪氨酸激酶 (RTK) 的人表皮生长因子受体 (HER) 家族经常发生改变在癌症中，对患者肿瘤的靶向组测序揭示了两者的许多激活改变。因此，出现了几代分子靶向 EGFR 和 HER2 疗法。已被设计并已被证明对一些患有 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 HER 家族变异子集仍然存在，并且在缺乏功能的情况下的功能数据被归类为意义不明的变体，目前尚不清楚是否所有 EGFR 和 HER2 错义突变是致癌驱动因素，对临床 EGFR 或 HER2 靶向治疗敏感。该提案旨在从功能和机械角度表征 EGFR 和 HER2 错义的作用目标 1 将寻求促进肿瘤发生和对酪氨酸激酶抑制剂 (TKI) 疗法产生耐药性的变异。为携带罕见 EGFR 突变且没有临床批准的 EGFR 的患者指定替代策略目标 2 将评估罕见 EGFR 变异的致癌能力。 HER2变异的致癌能力和TKI敏感性将受到极大质疑。提高我们对 RTK 错义变异如何促进癌症发展和耐药性的理解靶向治疗。 Hayes 博士将学习新技术，包括类器官培养、体内细胞系异种移植、胸腔内移植肺部注射、肿瘤成像和组织处理/染色，同时提升她的职业生涯在 K99 阶段，通过资助写作、科学传播和领导力方面的培训来发展。 Hayes 博士的研究和培训将在 Matthew Meyerson 博士的主要指导下进行。癌症基因组学领域的领导者，并将通过与高水平专家的合作来补充通量遗传筛查、临床基因组学、结构生物学和体内小鼠模型，以及由 Michael Eck 博士、William Hahn 博士、Pasi Janne 博士和 Carla Kim 博士组成的咨询委员会提供指导。