Therapeutic targeting of Fibroblast Growth Factor Receptors in Squamous Cancers

 描述（由申请方提供）：肺和头颈部鳞状细胞癌是常见的高致死性癌症，目前尚无获批的与遗传生物标志物相关的靶向治疗。我们以前的研究已经提名成纤维细胞生长因子受体（FGFR）作为这些疾病的候选治疗靶点，尽管FGFR抑制剂的临床活性迄今为止一直是适度的，尽管有几例显着的反应。本提案的目标是开发在鳞状细胞癌中使用FGFR抑制剂的优化策略，其中FGFR基因的扩增、突变和易位是常见的。长期目标是使FGFR靶向治疗在鳞状细胞癌中的成功临床应用成为可能，因为迫切需要为这些疾病引入有效的治疗方法。该提案的独特之处在于，它利用了Dana-Farber癌症研究所/哈佛癌症中心的广泛和新颖的资源，并结合了对癌细胞系、转基因小鼠模型、患者来源的异种移植物、新型FGFR拮抗剂和来自正在进行的FGFR抑制剂临床试验的患者标本的研究。拟定的具体目的是：1）使用细胞系和小鼠模型评价已知和新型复发性FGFR改变的致癌性和FGFR抑制剂敏感性，2）开发克服对FGFR激酶抑制的获得性耐药性的策略，和3）定义癌细胞系和患者标本中FGFR激酶改变和共依赖性的基因组背景，并评价靶向共依赖性的策略。这些研究将通过细胞模型系统、转基因动物和患者来源的异种移植物的开发和表征，确定在鳞状细胞癌患者中鉴定的哪些体细胞FGFR改变最有可能成为治疗靶点。对于经验证可赋予对FGFR抑制剂敏感性的FGFR改变，我们将使用来自FGFR抑制剂临床试验受试者的细胞和鼠模型以及肿瘤标本，以鉴定获得性耐药的机制并制定克服耐药的策略。在致癌FGFR改变不赋予对FGFR抑制的敏感性的情况下，我们将鉴定解释原发性耐药的基因组事件，并利用细胞和动物模型系统来定义通过靶向共依赖性克服耐药的方法。通过这些目标，我们打算确定临床应用FGFR抑制剂的最佳方法，最终目标是改善鳞状细胞癌患者的结局。

 DESCRIPTION (provided by applicant): Squamous cell carcinomas of the lung and head and neck are common and highly lethal cancers for which there are no approved targeted therapies associated with a genetic biomarker. Our previous studies have nominated Fibroblast Growth Factor Receptors (FGFRs) as candidate therapeutic targets in these diseases, though clinical activity of FGFR inhibitors has been modest to date despite a few cases of dramatic response. This goal of this proposal is to develop optimized strategies for the use of FGFR inhibitors in squamous cell carcinomas, in which amplification, mutation and translocation of FGFR genes are common. The long-term objective is to enable the successful clinical application of FGFR-targeted therapies in squamous cell cancers given the urgent need to introduce effective therapies for these diseases. This proposal is unique in that it leverages extensive and novel resources at the Dana-Farber Cancer Institute/Harvard Cancer Center and incorporates the study of cancer cell lines, transgenic mouse models, patient-derived xenografts, novel FGFR antagonists and patient specimens from ongoing clinical trials of FGFR inhibitors. The proposed Specific Aims are to: 1) Evaluate known and novel recurrent FGFR alterations for oncogenicity and FGFR inhibitor sensitivity using cell line and mouse models, 2) Develop strategies to overcome acquired resistance to FGFR kinase inhibition, and 3) Define the genomic context of FGFR kinase alterations and co-dependencies in cancer cell lines and patient specimens and evaluate strategies to target co-dependencies. These studies will define which somatic FGFR alterations identified in patients with squamous cell carcinomas are the most likely to be therapeutic targets through the development and characterization of cellular model systems, transgenic animals and patient-derived xenografts. For FGFR alterations validated to confer sensitivity to FGFR inhibitors we will use cellular and murine models and tumor specimens from subjects on clinical trials of FGFR inhibitors to identify mechanisms of acquired resistance and develop strategies to overcome resistance. In cases in which oncogenic FGFR alterations do not confer sensitivity to FGFR inhibition we will identify the genomic events accounting for primary resistance and utilize cellular and animal model systems to define approaches to overcome resistance by targeting co-dependencies. Through these Aims we intend to define the optimal ways in which to apply FGFR inhibitors clinically with the ultimate goal of improving outcomes for patients with squamous cell carcinomas.