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Characterizing and Targeting ERBB2 Mutations in Invasive Lobular Carcinoma

侵袭性小叶癌中 ERBB2 突变的特征和靶向

基本信息

批准号：
10749213
负责人：
Jie Bin Liu
金额：
$ 5.27万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749213
关键词：
Acceleration Antibody-drug conjugates Automobile Driving Breast Cadherins Cell Line Characteristics Clinical Clinical Management Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complement Data Dependence Disease Drug resistance E-Cadherin ERBB2 gene Engineering Environment Epidermal Growth Factor Receptor Estrogen receptor positive Evolution Exhibits FDA approved Future Genes Genetic Transcription Genomics Goals Growth Growth Factor Receptors HSP 90 inhibition Heat-Shock Proteins 90 Histologic IGF1R gene In Vitro Inferior Investigation Knock-out Learning Lobular Carcinoma Malignant Epithelial Cell Mediating Messenger RNA Metastatic breast cancer Molecular Molecular Chaperones Mutation Nature Nuclear Null Lymphocytes Oncogenic Organoids Outcome Patients Phenotype Physicians Plasma Pre-Clinical Model Prevalence Prognosis Receptor Protein-Tyrosine Kinases Recurrence Regulation Reporting Repression Research Personnel Resistance Role Sampling Scientist Signal Pathway Signal Transduction Specimen Testing The Cancer Genome Atlas Therapeutic Training Tyrosine Kinase Inhibitor Woman Xenograft procedure breast cancer progression clinically relevant clinically significant effective therapy experimental study gain of function genome editing hormone therapy in vitro Model infiltrating duct carcinoma innovation mRNA Expression malignant breast neoplasm mutant overexpression patient subsets permissiveness protein expression response targeted treatment therapy resistant transcriptome sequencing translational cancer research tumor tumor progression

项目摘要

PROJECT SUMMARY Although invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer, there remains much to be learned about the unique nature of this disease. Compared to invasive ductal carcinoma (IDC), ILC is understudied, with distinct histological, genomic, and clinical characteristics. Despite key differences, women with estrogen receptor-positive (ER+) ILC will most likely receive the same treatment as women with ER+ IDC though often show inferior long-term outcomes. Recently, the Lee-Oesterreich Lab and others have identified enrichment of ERBB2 mutations in ILC compared to IDC. As ILC is characterized by loss of CDH1 (E-cadherin), our findings may suggest a potential interaction between loss of CDH1 and mutations in ERBB2 in driving ILC tumor progression. As ERBB2 mutations usually occur in the absence of ERBB2 amplification, there are currently no FDA-approved therapies targeting ERBB2 mutant ILC. Several clinical trials have reported promising efficacy of anti-HER2 tyrosine kinase inhibitors, including neratinib, in patients with ERBB2 mutant ILC. However, resistance to these therapies is inevitable. In order to identify the most effective combination therapies, the functional role of these recurrent ERBB2 mutations in ILC requires further investigation. Using a combination of clinical specimens, innovative in vitro models and CRISPR-based genome editing, our proposal will determine the prevalence of ERBB2 mutations in ctDNA collected from plasma samples of patients with metastatic breast cancer and investigate how these mutations influence HER2 activation and downstream signaling pathways and sensitivity/resistance to available anti-HER2 agents (Aim 1). We will also evaluate the effects of CDH1 knockout and re-expression on HER2 signaling and degradation in order to understand the cooperation between loss of CDH1 and mutations in ERBB2 in ILC and explore potential mechanisms of HER2 regulation by E-cadherin (Aim 2). Results of this and future research will help inform clinicians and researchers of the mechanisms, clinical relevance, and targetability of recurrent ERBB2 mutations and complement findings from ongoing clinical trials to identify the most effective therapy combinations for patients with ERBB2 mutant ILC.

项目总结