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 SPORE 项目，由之前资助的 SPORE 试点项目演变而来。总体目标是开发成纤维细胞生长因子受体（FGFR）通路作为肺癌的治疗靶点。针对 EGFR 和 ALK 的酪氨酸激酶抑制剂 (TKI) 极大地影响了由这些受体酪氨酸激酶 (RTK) 致癌形式驱动的肺癌的治疗。尽管如此，很大一部分肺癌，特别是非腺癌组织学，尚未确定驱动癌基因，并且仍然是重要且未满足的临床需求。我们的研究揭示了 FGFR 通路在不同组织学的 NSCLC 细胞系中作为癌基因驱动因素的作用。尽管最近在鳞状肺癌中描述了 FGFR1 基因扩增和/或拷贝数增加，但 FGFR 依赖性的发生独立于功能获得性突变。此外，据报道，肺癌中存在 FGFR2 和 FGFR3 的罕见体细胞突变，尽管它们作为致癌基因驱动因素的潜力尚未确定。 FGFR1 基因拷贝数在 FGFR 特异性 TKI、AZD4547 和 BGJ398 的早期试验中被用作预选标记。虽然我们将进一步探索 FGFR1 拷贝数增益，但我们的临床前研究结果表明，其他预测生物标志物（FGFR1 mRNA 和蛋白表达）可能更准确地识别 FGFR 依赖性肺癌，因此识别 FGFR 特异性 TKI 敏感的肺癌。具体来说，我们已经证明 FGFR 活性取决于 FGFR1 的表达和配体 FGF2 或 FGF9 的共表达，从而建立自分泌机制来驱动 FGFR 活性增加。我们将检验以下假设：FGF-FGFR1 自分泌途径是肺癌所有组织学中常见的致癌驱动因素，并且 FGFR1 基因拷贝数之外的特定生物标志物将作为可能对 FGFR 选择性 TKI 产生反应的肺癌患者的预测生物标志物。为了检验这个假设，我们将完成以下具体目标。具体目标 1：定义生物标志物，准确识别具有激活的 FGFR 通路的肺癌子集。具体目标2：使用优化的生物标志物选择策略，对肺癌患者进行FGFR活性TKI ponatinib的II期临床试验。具体目标 3：确定 FGFR 特异性 TKI 获得性耐药机制。该项目的成功完成将揭示一种新颖且重要的肺部肿瘤子集，对整体肺癌治疗产生重大影响，这些肿瘤目前无法通过简单的突变筛查来识别，也无法通过批准的治疗方法来靶向。