Therapeutic targeting of Fibroblast Growth Factor Receptors in Squamous Cancers

鳞状癌中成纤维细胞生长因子受体的治疗靶向

• 批准号: 8938887
• 负责人: Peter S Hammerman
• 金额: $ 38.67万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8938887
• 关键词: Accounting; American Society of Clinical Oncology; Animal Model; Award; Biological Assay; Biological Markers; Biological Models; Cancer Center; Cancer cell line; Cell Culture Techniques; Cell Line; Cell model; Central Nervous System Neoplasms; Cessation of life; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Dana-Farber Cancer Institute; Data; Dependency; Development; Disease; Drug Combinations; Endometrial Carcinoma; Event; Failure; Family; Fibroblast Growth Factor Receptors; Gene Mutation; Genetic Markers; Genetically Engineered Mouse; Genomics; Goals; Growth Factor Receptor Genes; Head and Neck Squamous Cell Carcinoma; Head and neck structure; In Vitro; Incidence; Institution; Lead; Life; Lung; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of urinary bladder; Modeling; Mus; Mutation; Oncogenic; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Protein Tyrosine Kinase; Proto-Oncogenes; Public Health; Receptor Inhibition; Recurrence; Research Infrastructure; Resistance; Resistance development; Resources; Specimen; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Therapeutic; Transgenic Animals; Transgenic Mice; Treatment Efficacy; Treatment-Related Cancer; United States; Work; Xenograft Model; Xenograft procedure; base; cancer type; clinical application; clinical efficacy; effective therapy; improved; in vivo; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; metaplastic cell transformation; mortality; mouse model; novel; oncology; patient population; pre-clinical; preclinical study; programs; public health relevance; research study; resistance mechanism; response; success; targeted cancer therapy; targeted treatment; therapeutic target; tumor

 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.

 描述(申请人提供)：肺鳞癌和头颈部鳞状细胞癌是常见的高度致命的癌症，目前还没有批准的与遗传生物标记物相关的靶向治疗方法。我们之前的研究已经提名成纤维细胞生长因子受体(FGFRs)作为这些疾病的候选治疗靶点，尽管FGFR抑制剂的临床活性一直不高，尽管有少数病例发生了戏剧性的反应。这项建议的目标是开发FGFR抑制剂在鳞癌中使用的优化策略，在鳞状细胞癌中，FGFR基因的扩增、突变和易位是常见的。长期目标是使FGFR靶向疗法能够成功地应用于鳞癌的临床应用，因为迫切需要为这些疾病引入有效的疗法。这项建议的独特之处在于，它利用了达纳-法伯癌症研究所/哈佛癌症中心的广泛和新颖的资源，并纳入了对癌细胞系、转基因小鼠模型、患者来源的异种移植、新型FGFR拮抗剂和正在进行的FGFR抑制剂临床试验的患者样本的研究。建议的具体目标是：1)使用细胞系和小鼠模型评估已知和新的反复发生的FGFR改变的致瘤性和FGFR抑制剂的敏感性，2)开发克服获得性FGFR激酶抑制耐药的策略，以及3)确定癌细胞系和患者样本中FGFR激酶改变和相互依赖的基因组背景，并评估针对相互依赖的策略。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的发展和特征，确定在鳞癌患者中发现的哪些体细胞FGFR变化最有可能成为治疗靶点。对于被证实对FGFR抑制剂敏感的FGFR改变，我们将使用细胞和小鼠模型以及来自FGFR抑制剂临床试验受试者的肿瘤标本来识别获得性耐药的机制，并制定克服耐药的策略。在致癌的FGFR改变不会增加对FGFR抑制的敏感性的情况下，我们将确定导致原始耐药的基因组事件，并利用细胞和动物模型系统来定义通过靶向共同依赖来克服耐药的方法。通过这些目标，我们打算确定在临床上应用FGFR抑制剂的最佳方法，最终目标是改善鳞癌患者的预后。