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

基本信息

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
项目类别：
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

项目摘要

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（由申请人证明）：肺部和头颈的鳞状细胞癌是常见的，并且高度致命的癌症是与遗传生物标志物相关的靶向疗法，尽管FGFR抑制剂的临床活动是适度的尽管有一些戏剧性的响应案例。在鳞状细胞癌中，迫切需要对这些疾病引入疗法。，患者衍生的Xenographs，新型的FGFR拮抗剂和FGFR抑制剂持续临床的患者标本。克服对FGFR激酶抑制的抗药性的策略，以及3）定义FGFR激酶改变的基因组环境和癌细胞lins的共同依赖性以及患者和评估策略的靶向共依赖性。是针对细胞模型系统，转基因动物和患者衍生的Xenographs的特征，我们将在FGFR抑制剂的临床试验中使用细胞，模型和肿瘤标本克服抗性FGFR改变的原因。该患者的细胞癌患者在临床上使用Touth Toal Otcomes临床抑制FGFR抑制剂。