An FGFR1 oncogene driver pathway in head and neck cancer

头颈癌中的 FGFR1 致癌基因驱动通路

• 批准号: 8814998
• 负责人: LYNN E HEASLEY
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814998
• 关键词: Antibodies; Archives; Biological Assay; Biological Markers; Cell Line; Cetuximab; Clinical; Clinical Trials; Custom; Cytotoxic Chemotherapy; Data; Dependency; Development; Disease; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Essential Genes; FGF2 gene; FGFR1 gene; FGFR2 gene; FGFR3 gene; Failure; Fibroblast Growth Factor Receptors; Gefitinib; Genes; Genomic approach; Growth; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Health; Immune; In Vitro; Libraries; Malignant Epithelial Cell; Malignant Neoplasms; Molecular; Mus; Mutate; Mutation; Nude Mice; Oncogenes; Oncogenic; Pathway interactions; Patients; Population; Positioning Attribute; Prevalence; Primary Neoplasm; Proteoglycan; Publishing; RNA Interference; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Relapse; Resistance; Role; Signal Pathway; Specimen; Staging; Survival Rate; Testing; Therapeutic Monoclonal Antibodies; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Veterans; autocrine; base; cell killing; clinically relevant; functional genomics; head and neck cancer patient; in vitro testing; in vivo; inhibitor/antagonist; neoplastic cell; new therapeutic target; novel; paracrine; prognostic; receptor; resistance mechanism; response; small molecule; targeted treatment; therapeutic target; tumor

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide and despite optimized cytotoxic therapies, the 5-year survival rate of metastatic disease remains poor. Novel targets and therapies are clearly needed for disseminated disease. Receptor tyrosine kinases (RTKs) are attractive cancer targets due to: 1) frequent deregulation via mutation, amplification and/or autocrine/paracrine activation, 2) proximal positioning in oncogenic signal pathways and 3) specific targeting by small molecule tyrosine kinase inhibitors (TKIs) and inhibitory antibodies. To date, targeted therapies have not been effectively applied to HNSCC due, in part, to paucity of information on the dominant oncogene drivers. While the inhibitory EGFR antibody, cetuximab, is approved for use in HNSCC, overall effects are modest, likely due to failure to select for EGFR-addicted HNSCCs and/or rapid acquisition of resistance. While genomic approaches provide new information regarding tumor suppressors relevant to HNSCC, frequently mutated oncogene drivers were not generally identified. This observation raises the question of whether targeted therapeutics can, in fact, be successfully applied to this cancer. Our published findings identify a subset of HNSCC cell lines that is highly sensitive to FGFR inhibitors as well as a subset that is sensitive to EGFR-specific TKIs. In addition, our published and preliminary findings reveal putative roles for FGFRs in acquired resistance to EGFR-specific inhibitors. Together, these results support a hypothesis that an FGFR autocrine pathway is a dominant oncogene driver in a subset of HNSCCs. Moreover, specific FGFRs are candidates for acquired or intrinsic resistance mechanisms to EGFR inhibitors in HNSCC. To test these hypotheses, we will complete these Aims: Aim 1. Define the active FGFRs and FGFs that function as drivers in HNSCC cell lines and in primary HNSCC tumors directly propagated in nude mice. Also, the prevalence of FGFR pathway expression in archived HNSCC tumors will be defined. We will test the hypothesis that FGFR1 and specific FGFs and proteoglycan co-receptors are components of an oncogene driver pathway that functions in a clinically relevant fraction of head and neck tumors. Aim 2. Define FGFR-dependent and novel mechanisms of resistance to EGFR inhibitors in HNSCC. Our studies show rapid induction of FGFR2 and FGFR3 in EGFR- dependent HNSCC cells following treatment with EGFR-specific inhibitors as well as slower adaptive induction of FGFR1 and FGF2 during acquired resistance of EGFR-dependent HNSCC cell lines to gefitinib. We hypothesize that the failure of EGFR-targeted therapies to provide long-term control of HNSCC is due to multiple auxiliary growth pathways that reduce efficacy of EGFR inhibition alone. Completion of these specific aims is anticipated to unveil FGFR pathways as novel therapeutic targets in HNSCC. The ongoing early clinical development of multiple FGFR inhibitors could set the stage for their rapid application to this cancer that is highly relevant to the veteran population.

描述（由申请人提供）： 头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症，尽管优化了细胞毒性疗法，但转移性疾病的 5 年生存率仍然很低。传播性疾病显然需要新的靶点和疗法。受体酪氨酸激酶 (RTK) 是有吸引力的癌症靶点，因为：1) 通过突变、扩增和/或自分泌/旁分泌激活频繁地失调，2) 在致癌信号通路中的近端定位，以及 3) 小分子酪氨酸激酶抑制剂 (TKI) 和抑制性抗体的特异性靶向。迄今为止，靶向治疗尚未有效应用于 HNSCC，部分原因是缺乏有关主要致癌基因驱动因素的信息。虽然抑制性 EGFR 抗体西妥昔单抗已被批准用于 HNSCC，但总体效果不大，可能是由于未能选择 EGFR 成瘾的 HNSCC 和/或快速获得耐药性。虽然基因组方法提供了与 HNSCC 相关的肿瘤抑制因子的新信息，但经常突变的癌基因驱动因素尚未被普遍识别。这一观察结果提出了一个问题：靶向治疗实际上是否可以成功应用于这种癌症。我们发表的研究结果确定了对 FGFR 抑制剂高度敏感的 HNSCC 细胞系子集以及对 EGFR 特异性 TKI 敏感的子集。此外，我们发表的初步研究结果揭示了 FGFR 在 EGFR 特异性抑制剂获得性耐药中的假定作用。总之，这些结果支持了这样一个假设：FGFR 自分泌途径是 HNSCC 子集中的主要致癌基因驱动因素。此外，特定的 FGFR 是 HNSCC 中 EGFR 抑制剂获得性或内在耐药机制的候选者。为了测试这些假设，我们将完成以下目标： 目标 1. 定义在 HNSCC 细胞系和直接在裸鼠中增殖的原发性 HNSCC 肿瘤中充当驱动程序的活性 FGFR 和 FGF。此外，还将定义存档的 HNSCC 肿瘤中 FGFR 通路表达的流行率。我们将检验以下假设：FGFR1 和特定 FGF 以及蛋白聚糖共受体是癌基因驱动通路的组成部分，该通路在头颈肿瘤的临床相关部分中发挥作用。目标 2. 定义 HNSCC 中 FGFR 依赖性的 EGFR 抑制剂耐药新机制。我们的研究表明，用 EGFR 特异性抑制剂治疗后，EGFR 依赖性 HNSCC 细胞中 FGFR2 和 FGFR3 会快速诱导，而 EGFR 依赖性 HNSCC 细胞系对吉非替尼获得性耐药期间，FGFR1 和 FGF2 的适应性诱导会较慢。我们假设 EGFR 靶向疗法未能长期控制 HNSCC 是由于多种辅助生长途径降低了单独抑制 EGFR 的疗效。这些具体目标的完成预计将揭示 FGFR 通路作为 HNSCC 的新治疗靶点。多种 FGFR 抑制剂正在进行的早期临床开发可能为其快速应用于这种与退伍军人群体高度相关的癌症奠定基础。