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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：
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.

总结表皮生长因子受体（EGFR）仍然是头颈部唯一有效的分子靶点鳞状细胞癌（HNSCC），介导细胞存活信号传导和对放射疗法的抗性。尽管EGFR靶向治疗如西妥昔单抗取得了成功，最终发展。改善EGFR靶向治疗的一个重大挑战是在临床上识别和治疗EGFR靶向治疗。验证治疗抗性的可行机制。在这份提案中，我们设计了一项战略，在基础科学研究、临床前测试和临床样本测试之间进行迭代，以阐明 HNSCC中西妥昔单抗耐药的机制。使用体外方法分析西妥昔单抗耐药性，我们鉴定了靶向自分泌配体NRG-1的上调作为耐药的靶机制。我们利用小鼠异种移植研究，在细胞系和体内模拟了这种耐药性，它可以通过使用ErbB 3靶向抗体治疗剂（CDX-3379）在治疗上逆转，可以恢复对西妥昔单抗和放射治疗的反应。我们还观察到NRG-1诱导的抗性小分子EGFR激酶抑制剂在癌细胞中的作用，并研究了这种作用的机制起源。在结构层面的阻力。我们建议利用这一新知识，在HNSCC中靶向EGFR家族成员的方法。在这些研究的同时，我们将研究临床来自正在进行的阿法替尼+西妥昔单抗II期HNSCC试验的标本，以及两项ECOG试验，西妥昔单抗，研究临床耐药机制。我们还将开发患者来源的异种移植物 (PDX)来自正在进行的临床试验的模型，以测试耐药机制的假设并评估为克服这一问题而制定的新战略的有效性。该提案的关键前提是，了解西妥昔单抗耐药机制将打开新的治疗机会-使我们能够开发出在西妥昔单抗治疗时仍然可以抑制EGFR的方法，失败，并开发以西妥昔单抗不敏感方式激活EGFR的其他分子为靶点的方法 (such作为ErbB 3）。我们的三个具体目标是： 1.为了阐明HNSCC中西妥昔单抗耐药的机制并建立模型，并测试CDX-3379作为新的抗肿瘤药物。 ErbB 3靶向方法用于增强HNSCC中的全身和/或放射治疗。 2.为了开发新的结构/机制指导的策略，成功地用小分子药物靶向ErbB受体，分子酪氨酸激酶抑制剂（TKI）。 3.使用临床试验样本鉴定ErbB靶向治疗的治疗应答生物标志物，建立平行的患者源性肿瘤模型，以评估对ErbB靶向药物的耐药机制 HNSCC的治疗