权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting FGFR and EGFR in Bladder Cancer

靶向 FGFR 和 EGFR 在膀胱癌中的作用

基本信息

批准号：
8230254
负责人：
COLIN P.N. DINNEY
金额：
$ 20.32万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230254
关键词：
Antibodies Apoptosis Area Biological Biological Markers Biological Process Bladder Cancer cell line Cell Line Cell Proliferation Cells Clinical Clinical Trials Data Dependency Dose Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Exhibits FGF2 gene FGFR3 gene Fibroblast Growth Factor Fibroblast Growth Factor 2 Fibroblast Growth Factor Receptors Fibroblasts Gefitinib Gene Expression Gene Expression Profiling Genes Genomics Goals Growth In Vitro Intracellular Membranes Laboratory Study Lead Learning Ligands Malignant Neoplasms Malignant neoplasm of urinary bladder Maps Measures Mesenchymal Mesenchymal Cell Neoplasm Methods Modeling Muscle Mutation Neoadjuvant Therapy Organ Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Play Pre-Clinical Model Primary Neoplasm Process Protein Kinase Research Resistance Risk Role Signal Transduction Testing Therapeutic Tissues Toxic effect Translations Tumor Suppressor Genes Universities Urogenital Cancer Urothelial Cell Xenograft procedure angiogenesis autocrine base cancer cell cancer therapy design epithelial to mesenchymal transition inhibitor/antagonist mutant neoplastic cell novel overexpression paracrine phase 2 study preclinical study receptor research study response small molecule therapeutic target tissue culture tumor

项目摘要

Tumors that express mutant protein kinases are usually dependent upon them for growth and survival. Activating mutations in FGFR3 occur in over half of low-grade non-muscle invasive bladder cancers (BCs) and in a quarter of muscle-invasive tumors, and small molecule and antibody-based FGFR3 inhibitors have exhibited potent growth-inhibitory activities in some BC cell lines and xenografts in preclinical studies. However, clinical translation of these observations has not occurred, in part because dose escalation trials have revealed that FGFR inhibitors produce some toxicity, and whether the extent of target inhibition at non-toxic doses is sufficient to produce apoptosis and/or growth arrest is not clear. We have assembled a collaborative group involving the GU Cancers team at Astra-Zeneca and Dr. Margaret Knowles (University of Leeds, UK) to conclusively determine the value of FGFR3 as a therapeutic target in BC. Our approach will be to use our unique panel of cell lines and xenografts to (1) isolate biomarkers that predict FGFR3 dependency better than FGFR3 mutational status alone and (2) develop pharmacodynamic approaches to determine the extent of tumor FGFR3 pathway inhibition and correlate it with biological response. We will also explore the effects of the novel tumor suppressive "forerunner" gene ARL11 on Ras pathway activation and define the relationships between ARL11 downregulatlon, FGFR3 and Ras mutational status, and Ras pathway activation in primary tumors, studies that are based on novel findings obtained in Project 1. We will then perform a neoadjuvant clinical trial to determine whether the doses of AZD4547 that can be safely achieved in patients produce sufficient target inhibition to cause apoptosis and/or growth arrest in primary tumors. This methodical approach will provide the strong mechanistic information required for the intelligent design of subsequent Phase II studies in low-grade and muscle-invasive BCs as well as in hematological and other tumors.

表达突变蛋白激酶的肿瘤通常依赖于它们的生长和存活。