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Project 1: Improved Targeting of EGFR Family Members in Squamous Cell Carcinomas of the Head and Neck

项目 1：改进 EGFR 家族成员在头颈鳞状细胞癌中的靶向作用

基本信息

批准号：
10668978
负责人：
Mark A Lemmon
金额：
$ 35.71万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668978
关键词：
Address Antibodies Basic Science Biochemical Biological Models Biophysics Cell Line Cell Survival Cells Cetuximab Clinic Clinical Clinical Trials Dependence ERBB3 gene Eastern Cooperative Oncology Group Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epitopes Event Family Family member Generations Genetic Genetic Markers Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure In Vitro Investigation Knowledge Learning Ligands Malignant neoplasm of lung Mediating Modeling Molecular Molecular Conformation Molecular Target Mus Mutation Neuregulin 1 Patients Phase Phase II Clinical Trials Pre-Clinical Model Preclinical Testing Radiation therapy Receptor Signaling Resistance Sampling Signal Transduction Specimen Structure Systemic Therapy Testing Therapeutic Therapeutic Uses Therapeutic antibodies Tissues Tumor Markers Tumor-infiltrating immune cells Tyrosine Kinase Inhibitor Up-Regulation Work Xenograft Model Xenograft procedure autocrine biobank biomarker identification cancer cell clinical translation co-clinical trial design effectiveness evaluation efficacy testing exome sequencing improved in vivo inhibitor kinase inhibitor model design novel novel strategies novel therapeutic intervention novel therapeutics participant enrollment patient derived xenograft model preference preservation prevent radiation response receptor resistance mechanism response small molecule success targeted treatment therapy resistant treatment response tumor

项目摘要

SUMMARY The epidermal growth factor receptor (EGFR) remains the only validated molecular target in head and neck squamous cell carcinoma (HNSCC), mediating cell survival signaling and resistance to radiation therapy. despite the success of EGFR targeted therapies such as cetuximab, therapeutic resistance to EGFR targeting ultimately develops. A significant challenge for improving EGFR targeted therapies is to identify and clinically validate actionable mechanisms of therapeutic resistance. In this proposal, we have designed a strategy that iterates between basic science investigations, preclinical testing, and clinical specimen testing to elucidate the mechanism of cetuximab resistance in HNSCC. Using an in vitro approach for analyzing cetuximab resistance, we identified upregulation of a targetable autocrine ligand, NRG-1, as a target mechanism of resistance. We have modeled this resistance both in cell lines and in vivo, using mouse xenograft studies, and have shown that it can be reversed therapeutically by using an ErbB3-targeted antibody therapeutic (CDX-3379) – which can restore responses to cetuximab and radiation therapy. We have also observed NRG-1-induced resistance to small molecule EGFR kinase inhibitors in cancer cells, and have studied the mechanistic origin of this resistance at a structural level. We propose to exploit this new knowledge to advance small molecular approaches for targeting EGFR family members in HNSCC. In parallel with these studies, we will study clinical specimens from an ongoing phase II HNSCC trial of afatinib plus cetuximab, plus two ECOG trials of cetuximab, to investigate resistance mechanisms in the clinic. We will also develop patient-derived xenografts (PDX) models from the ongoing clinical trial to test hypotheses for resistance mechanisms and to assess effectiveness of new strategies devised to overcome it. The key premise of the proposal is that understanding mechanisms of resistance to cetuximab will open up new therapeutic opportunities – allowing us to develop approaches that can still inhibit EGFR when cetuximab fails, and to develop approaches to target other molecules that activate EGFR in a cetuximab-insensitive way (such as ErbB3). Our three Specific Aims are: 1. To elucidate and model mechanisms of cetuximab resistance in HNSCC, and to test CDX-3379 as a new ErbB3 targeted approach for enhancing systemic and/or radiation therapy in HNSCC. 2. To develop new structure/mechanism-guided strategies for successful ErbB-receptor targeting with small molecule tyrosine kinase inhibitors (TKIs) in HNSCC. 3. To identify biomarkers of therapeutic response to ErbB-targeted therapies using clinical trial samples, and to establish parallel patient-derived tumor models to evaluate mechanisms of resistance to ErbB-targeted therapies in HNSCC.

总结