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取决于它们的生长和生存。 FGFR3中的激活突变发生在低度非肌肉浸润性膀胱癌（BCS）的一半以上。在四分之一的肌肉侵入性肿瘤中，小分子和基于抗体的FGFR3抑制剂具有在临床前研究中，在某些BC细胞系和异种移植物中表现出有效的抑制活性。但是，这些观察结果的临床翻译尚未发生，部分原因是剂量升级试验已经揭示了FGFR抑制剂会产生一些毒性，以及目标抑制的程度是否在无毒剂量足以产生凋亡和/或生长停滞尚不清楚。我们已经组装了涉及Astra-Zeneca的GU Cancers团队和玛格丽特·诺尔斯博士（大学）的合作小组英国利兹的of）最终确定FGFR3作为卑诗省的治疗靶标的价值。我们的方法将使用我们独特的细胞系和异种移植面板对（1）预测FGFR3的分离物生物标志物依赖性比单独的FGFR3突变状态更好，（2）开发药效方法确定肿瘤FGFR3途径抑制的程度，并将其与生物反应相关。我们将还探索新型肿瘤抑制“先驱”基因ARL11对RAS途径的影响激活和定义ARL11下调，FGFR3和RAS突变状态之间的关系，原发性肿瘤中的RAS途径激活，基于项目中获得的新发现的研究 1。然后，我们将进行新辅助临床试验，以确定是否可以是AZD4547的剂量在患者中安全实现的实现会产生足够的靶标抑制，以引起凋亡和/或生长停滞原发性肿瘤。这种有条理的方法将提供强大的机械信息随后在低级和肌肉侵入性BC的II期研究的智能设计以及血液学和其他肿瘤。