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生存。 超过一半的低级别非肌肉浸润性膀胱癌(BCS)中存在FGFR3的激活突变 在四分之一的肌肉侵袭性肿瘤中，基于小分子和抗体的FGFR3抑制剂 在一些BC细胞株和异种移植瘤中，在临床前研究中显示出强烈的生长抑制活性。 然而，这些观察结果的临床翻译尚未发生，部分原因是剂量递增试验 已经揭示了FGFR抑制剂产生一定的毒性，以及靶向抑制的程度是否在 无毒剂量是否足以导致细胞凋亡和/或生长停滞尚不清楚。我们已经组建了一支 由阿斯特拉-捷利康GU癌症团队和玛格丽特·诺尔斯博士(大学)组成的合作小组 最终确定FGFR3作为BC治疗靶点的价值。我们的方法 将使用我们独特的细胞系和异种移植小组来(1)分离预测FGFR3的生物标记物 依赖比单独的FGFR3突变状态更好；(2)开发药效学方法 确定肿瘤FGFR3通路的抑制程度，并与生物学反应相关联。我们会 同时探讨新的抑癌基因ARL11对RAS通路的影响 激活并确定ARL11下调、FGFR3和RAS突变状态之间的关系， 和RAS通路在原发肿瘤中的激活，这些研究基于在Project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AZD4547的剂量是否可以 在患者中安全地实现产生足够的靶向抑制以导致细胞凋亡和/或生长停滞 原发肿瘤。这种有条不紊的方法将提供所需的强有力的机械信息 低级别和肌肉侵袭性BCS以及 血液病和其他肿瘤。

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.