Targeting FGFR and EGFR in Bladder Cancer

表达突变蛋白激酶的肿瘤通常依赖于它们的生长和存活。 FGFR 3的激活突变发生在超过一半的低度非肌肉浸润性膀胱癌（BC）中 在四分之一的肌肉浸润性肿瘤中，小分子和基于抗体的FGFR 3抑制剂 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生长抑制活性。 然而，这些观察结果的临床转化尚未发生，部分原因是剂量递增试验 已经揭示了FGFR抑制剂产生一些毒性，并且是否靶向抑制的程度在 无毒剂量是否足以产生细胞凋亡和/或生长停滞尚不清楚。我们组建了一个 阿斯利康GU癌症团队和玛格丽特·诺尔斯博士（大学） of利兹，英国），以最终确定FGFR 3作为BC中治疗靶标的价值。我们的方法 将使用我们独特的细胞系和异种移植物组（1）分离预测FGFR 3的生物标志物 依赖性优于单独的FGFR 3突变状态和（2）开发药效学方法， 确定肿瘤FGFR 3通路抑制的程度并将其与生物学反应相关联。我们将 并探讨新的肿瘤抑制“先导”基因ARL 11对Ras通路的影响 激活并定义ARL 11下调、FGFR 3和Ras突变状态之间的关系， 和Ras通路激活，这些研究是基于项目中获得的新发现， 1.然后，我们将进行新辅助临床试验，以确定AZD 4547的剂量是否可以 在患者中安全实现，产生足够的靶向抑制，导致细胞凋亡和/或生长停滞， 原发性肿瘤这种有条理的方法将提供所需的强有力的机械信息， 智能设计随后的II期研究，在低度和肌肉侵入性BC以及 血液和其他肿瘤。

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.