Targeting FGFR1 Signaling in Lung Cancer

靶向肺癌中的 FGFR1 信号传导

• 批准号: 8664636
• 负责人: LYNN E HEASLEY
• 金额: $ 27.49万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8664636
• 关键词: Archives; Automobile Driving; Biological Assay; Biological Markers; Biopsy Specimen; Cancer Histology; Cancer Patient; Cancer cell line; Cell Line; Characteristics; Clinical; Clinical Trials; Clinical Trials Design; Custom; Data; Dependence; Dependency; Disease; Enrollment; Epidermal Growth Factor Receptor; Exhibits; FGF2 gene; FGF9 gene; FGFR1 Gene Amplification; FGFR1 gene; FGFR2 gene; FGFR3 gene; FGFR4 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Formalin; Funding; Gene Amplification; Gene Dosage; Gene Fusion; Genes; Goals; Growth; Histology; Immunohistochemistry; In Situ Hybridization; Libraries; Ligands; Lung Neoplasms; Malignant neoplasm of lung; Measures; Messenger RNA; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Outcome; Paraffin Embedding; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Pilot Projects; Proteins; Proteoglycan; Receptor Protein-Tyrosine Kinases; Relative (related person); Reporting; Resistance; Role; Series; Signal Transduction; Silver; Somatic Mutation; Techniques; Testing; Therapeutic; Tumor Tissue; Tyrosine Kinase Inhibitor; Xenograft Model; autocrine; base; cancer therapy; cohort; functional genomics; gain of function mutation; improved; in vitro testing; in vivo; inhibitor/antagonist; mRNA Expression; novel; patient population; pre-clinical; prognostic; protein expression; receptor; research clinical testing; response; screening; small molecule; therapeutic target; tumor; tumorigenesis

This is a new SPORE project that evolved from a previously-funded SPORE Pilot project. The overall goal is to develop the Fibroblast Growth Factor Receptor (FGFR) pathway as a therapeutic target in lung cancers. Tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK have greatly impacted the treatment of lung cancers driven by oncogenic forms of these receptor tyrosine kinases (RTKs). Still, a large fraction of lung cancers, especially of non-adenocarcinoma histologies, have no identified driving oncogene and remain an important and unmet clinical need. Our studies have unveiled a role for an FGFR pathway as an oncogene driver in NSCLC cell lines of diverse histologies. FGFR-dependency occurs independently of gain-of-function mutations, although FGFR1 gene amplification and/or copy number gain have recently been described in squamous lung cancers. In addition, rare somatic mutations in FGFR2 and FGFR3 have been reported in lung cancers, although their potential as oncogene drivers has not been defined. FGFR1 gene copy number is being employed as a pre-selection marker in early phase trials of the FGFR-specific TKIs, AZD4547 and BGJ398. While we will further explore FGFR1 copy number gain, our preclinical findings reveal that other predictive biomarkers (FGFR1 mRNA and protein expression) may more accurately identify FGFR-dependent, and therefore FGFR-specific TKI sensitive, lung cancers. Specifically, we have shown that FGFR activity depends on expression of FGFR1 and co-expression of the ligands, FGF2 or FGF9, thereby establishing an autocrine mechanism to drive increased FGFR activity. We will test the hypothesis that an FGF-FGFR1 autocrine pathway serves as a frequent oncogenic driver across all histologies of lung cancers and that specific biomarkers beyond FGFR1 gene copy number will serve as predictive biomarkers of lung cancer patients likely to respond to FGFR-selective TKIs. To test this hypothesis, we will complete the following specific aims. Specific Aim 1: Define biomarkers that accurately identify the subset of lung cancers bearing activated FGFR pathways. Specific Aim 2: Use optimized biomarker selection strategies to conduct a phase II clinical trial with the FGFR-active TKI, ponatinib in lung cancer patients. Specific Aim 3: Identify mechanisms of acquired resistance to FGFR-specific TKIs. Successful completion of this project will exert high impact on overall lung cancer treatment by unveiling a novel and substantial subset of lung tumors that are not presently identifiable through simple mutation screening nor targetable by an approved therapeutic.

这是一个新的孢子项目，它是从先前资助的孢子试点项目中演变而来的。总体目标是将成纤维细胞生长因子受体（FGFR）途径发展为肺癌的治疗靶标。靶向EGFR和ALK的酪氨酸激酶抑制剂（TKI）极大地影响了这些受体酪氨酸激酶（RTKS）的致癌形式驱动的肺癌的治疗。尽管如此，很大一部分的肺癌，特别是非腺癌组织学的肺癌，尚未鉴定出驱动癌基因，并且仍然是重要且未满足的临床需求。我们的研究已经在不同组织学的NSCLC细胞系中揭示了FGFR途径的作用。尽管FGFR1基因扩增和/或拷贝数增长最近在鳞状肺癌中描述了FGFR1基因扩增和/或拷贝数增长，但FGFR依赖性独立于功能增益突变。此外，尽管尚未确定它们作为癌基因驱动因素的潜力，但在肺癌中据报道了FGFR2和FGFR3中罕见的体细胞突变。 FGFR1基因拷贝数被用作FGFR特异性TKI，AZD4547和BGJ398的早期试验中的预选标记。虽然我们将进一步探索FGFR1拷贝数的增益，但我们的临床前发现表明，其他预测性生物标志物（FGFR1 mRNA和蛋白质表达）可能更准确地鉴定出FGFR依赖性，因此FGFR特异性TKI敏感的肺癌。具体而言，我们已经表明FGFR活性取决于FGFR1的表达和配体FGF2或FGF9的共表达，从而建立了一种自分泌机制来驱动增加FGFR活性。我们将检验以下假设：FGF-FGFR1自分泌途径在肺癌的所有组织学中都是常见的致癌驱动因素，而FGFR1基因拷贝数以外的特定生物标志物将充当可能对FGFR Selective TKIS响应的肺癌患者的预测生物标志物。为了检验这一假设，我们将完成以下特定目标。特定目标1：定义生物标志物，以准确识别带有活化FGFR途径的肺癌的子集。具体目标2：使用优化的生物标志物选择策略在肺癌患者中使用FGFR活性TKI，Ponatinib进行II期临床试验。特定目标3：确定获得对FGFR特异性TKI的抗性的机制。该项目的成功完成将对整体肺癌治疗产生很大的影响，通过揭示新的和大量的肺部肿瘤子集，这些肺部肿瘤目前无法通过简单的突变筛查而被批准的治疗方法来识别。