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: 8544051
• 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/8544051
• 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; Genomics; Growth; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; 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; public health relevance; receptor; resistance mechanism; response; small molecule; 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）： 头部和颈部鳞状细胞癌（HNSCC）是全球第六次最常见的癌症，尽管进行了优化的细胞毒性疗法，但转移性疾病的5年生存率仍然很差。显然需要新的靶标和疗法来进行传播疾病。受体酪氨酸激酶（RTKS）是有吸引力的癌症靶标，因为：1）通过突变，扩增和/或自分泌/旁分泌激活频繁放松管制，2）在致癌信号途径中近端定位，以及3）小分子酪氨酸酪氨酸酪氨酸酶抑制剂（TKIS）和抑制性抗生素的特异性靶标。迄今为止，尚未有效地将有针对性的疗法应用于HNSCC，部分原因是缺少有关主要的癌基因驱动因素的信息。尽管抑制性EGFR抗体Cetuximab被批准用于HNSCC，但总体效果是适度的，这可能是由于未能选择EGFR添加的HNSCCS和/或快速获取阻力。尽管基因组方法提供了有关与HNSCC相关的肿瘤抑制剂的新信息，但通常未识别出常见突变的癌基因驱动因素。该观察结果提出了一个问题，即实际上是否可以成功地将靶向治疗剂应用于该癌症。我们已发表的发现确定了对FGFR抑制剂高度敏感的HNSCC细胞系的子集以及对EGFR特异性TKIS敏感的子集。此外，我们发表的初步发现揭示了FGFR在获得EGFR特异性抑制剂的抗性中的推定作用。总之，这些结果支持了一个假设，即FGFR自分泌途径是HNSCCS子集中的主要癌基因驱动器。此外，特定的FGFR是HNSCC中获得或内在电阻机制的候选者。为了检验这些假设，我们将完成这些目标：目标1。定义在HNSCC细胞系中充当驱动因素的活动FGFR和FGF，以及直接在裸体小鼠中直接传播的原发性HNSCC肿瘤中。同样，将定义存档HNSCC肿瘤中FGFR途径表达的流行率。我们将检验以下假设：FGFR1以及特定的FGF和蛋白聚糖共受体是癌基因驱动程序途径的组成部分，该途径在临床上相关的头颈肿瘤中起作用。 AIM 2。定义HNSCC中对EGFR抑制剂抗性的FGFR依赖性和新型机制。我们的研究表明，用EGFR特异性抑制剂处理后，EGFR依赖性HNSCC细胞中FGFR2和FGFR3的迅速诱导，以及在获得EGFR依赖性HNSCC细胞系对Gefitinib的EGFR依赖性HNSCC细胞中获得的耐药性，对FGFR1和FGF2的适应性降低。我们假设，EGFR靶向疗法的长期控制HNSCC的失败是由于多种辅助生长途径，仅降低了EGFR抑制的疗效。预计这些特定目标的完成将公布FGFR途径作为HNSCC的新型治疗靶标。多种FGFR抑制剂的持续早期临床发展可能为与退伍军人人群高度相关的癌症的快速应用奠定了基础。