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：
10267847
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/10267847
关键词：
Address Antibodies Basic Science Biochemical Biological Markers Biological Models Biophysics Cell Line Cell Survival Cells Cetuximab Clinic Clinical Clinical Trials Dependence ERBB3 gene Eastern Cooperative Oncology Group Engineering Enrollment 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 Ligands Malignant neoplasm of lung Mediating Modeling Molecular Molecular Conformation Molecular Structure 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-Derived Tumor-infiltrating immune cells Tyrosine Kinase Inhibitor Up-Regulation Work Xenograft Model Xenograft procedure autocrine base biobank cancer cell clinical translation design effectiveness evaluation efficacy testing exome sequencing improved in vivo inhibitor/antagonist kinase inhibitor model design novel novel strategies novel therapeutic intervention novel therapeutics 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.

概括表皮生长因子受体（EGFR）仍然是头部和颈部验证的分子靶标鳞状细胞癌（HNSCC），介导细胞存活信号传导和对放射治疗的抗性。尽管EGFR靶向疗法（例如西妥昔单抗）成功，但对EGFR靶向的治疗性抗性最终发展。在此提案中验证治疗性的可行机制。在基础科学研究，临床前测试和临床标本测试之间进行迭代以阐明您 HNSCC中西妥昔单抗的机理。我们将靶向自分泌配体NRG-1的上调视为Risisistanece的目标机制使用小鼠Xenographto研究对细胞lin和体内的这种抗性进行了建模，并已显示可以通过使用Anerbb3靶向抗体治疗（CDX-3379）进行治疗逆转 - 可以恢复对西妥昔单抗和放射治疗的反应。到癌细胞中的小分子EGFR激酶抑制剂，并研究了他的机械起源在结构水平上的电阻。针对HNSCC的EGFR家庭成员的方法。 Afatinib的Anning II HNSCC试验的标本加上Cetuximab，以及两个ECOG试验西妥昔单抗，研究诊所中的抗药性机制。（PDX）来自正在进行的临床测试假设的抗性机制的模型，并评估设计为克服它的新策略的有效性。该提议的主要前提是，对西妥昔单抗的抵抗力将开放新的治疗机会 - 允许我们开发出在西妥昔单抗时仍可以抑制EGFR的方法失败并开发方法以靶向其他以Cetuximab启示的方式激活EGFR的分子（例如ERBB3）。 1。阐明HNSCC中西妥昔单抗抗性的机理，并测试CDX-3379作为新的 ERBB3在HNSCC中增强全身和/或放射疗法的靶向方法。 2。开发新的结构/机制指导的策略，以实现成功的ERBB受体靶向 HNSCC中的分子酪氨酸激酶抑制剂（TKI）。 3。鉴定使用Clial样品对ERBB靶向疗法的治疗反应的生物标志物，并建立平行的患者来源的肿瘤模型，以评估对ERBB靶向的抗性机制 HNSCC的疗法。