Investigating the Role of the Tumor MicroEnvironment in Resistance of Urothelial Carcinoma of the Bladder to FGFR3 Inhibition

项目摘要 膀胱尿路上皮癌(即膀胱癌)是最常见的原发肿瘤。 尿路上皮道。膀胱癌的复发和转移仍然很常见，是导致 患者发病率和死亡率。尽管复发和转移的发生率很高，但没有新的治疗方法 在过去的三十年里，已经引入了针对晚期疾病的选择。许多患者最初 对治疗标准的反应在几年内表现出顽固性疾病。此外，患有 转移性疾病在诊断时往往表现出对标准护理治疗的抵抗力。 这些病例强调了对新疗法的迫切需要。新疗法的一个潜在靶点是成纤维细胞 生长因子受体3(FGFR3)，在膀胱癌中频繁突变。成纤维细胞生长因子受体3的体外研究 抑制剂显示了令人振奋的结果，然而，体内反应较温和。目前，它是 尚不清楚是什么在体内调节了对FGFR3抑制的反应，但我假设微环境是 参与了膀胱癌的耐药机制。 这项建议的目标是更好地了解肿瘤微环境在 膀胱癌对成纤维细胞生长因子受体3抑制的耐药性整体而言 假说是肿瘤微环境的成分赋予了对FGFR3抑制和 促进膀胱癌的转移，这种反应可能取决于细胞分化状态。这 假说将通过使用微环境微阵列(MEMA)进行验证，微环境微阵列由机器人组成 由功能性细胞外基质(ECM)组件组合而成的印刷生长垫， 在不同的局部和转移微环境中发现的因子和细胞因子，允许系统性 以理性还原的方式评估微环境对细胞表型的影响。基于 初步数据，本提案的具体目的如下：(1)确定 微环境在抵抗FGFR3抑制膀胱癌中的作用，以及(2)探讨 微环境在FGFR3抑制后分化状态标志物的表达中起作用 膀胱癌。这项提案的结果有可能提供新的信息，使我们能够 设计新的有针对性的方法，旨在预测或克服对FGFR3抑制和 预防这种疾病的转移。因此，这个项目有可能极大地影响膀胱癌。 患者的生活质量和总体生存。

Project Summary Urothelial carcinoma of the bladder (i.e. bladder cancer) is the most common primary tumor of the urothelial tract. Bladder cancer recurrence and metastases remain common and are significant contributors to patient morbidity and mortality. Despite the high prevalence of recurrence and metastasis, no new treatment options have been introduced for advanced disease in the past three decades. Many patients who initially respond to standard of care treatment exhibit refractory disease within a few years. Furthermore, patients with metastatic disease at the time of diagnosis often exhibit resistance to standard of care therapeutic treatment. These cases underscore the urgent need for new therapies. One potential target for new therapy is fibroblast growth factor receptor 3 (FGFR3), which is frequently mutated in bladder cancer. In vitro studies with FGFR3 inhibitors showed promising results, however, the in vivo responses were more modest. Currently, it is unknown what modulates response to FGFR3 inhibition in vivo, but I hypothesize that the microenvironment is contributing to resistance mechanisms in bladder cancer. The goal of this proposal is to better understand the roles that the tumor microenvironment plays in resistance of bladder cancers to Fibroblast Growth Factor Receptor 3 (FGFR3) inhibition. The overall hypothesis is that constituents of the tumor microenvironment confer resistance to FGFR3 inhibition and promote metastasis in bladder cancer, and that response may depend on cellular differentiation state. This hypothesis will be tested by employing MicroEnvironment MicroArrays (MEMA), which consists of robotically printed growth pads made up of combinations of functional extracellular matrix (ECM) components, growth factors and cytokines found in different local and metastatic microenvironments, allowing for systematic assessment of microenvironment effects on cellular phenotypes in a rational reductionist manner. Based on preliminary data, the specific aims of this proposal are as follows: (1) Determine the role that the microenvironment plays in resistance to FGFR3 inhibition in bladder cancer, and (2) Investigate the role that the microenvironment plays in expression of differentiation state markers in response to FGFR3 inhibition in bladder cancer. Results from this proposal have the potential to provide new information that will enable us to devise novel targeted approaches aimed at anticipating or overcoming resistance to FGFR3 inhibition and preventing metastases in this disease. Thus, this project has the potential to greatly impact bladder cancer patients' quality of life and overall survival.