Investigating G-protein coupled receptors (GPCRs) as biomarkers of aggressive

尤文肉瘤家族肿瘤(EFT)是高度恶性的骨和软组织肿瘤，主要影响 儿童、青少年和青壮年。尽管采取了激进的本地控制措施和系统性的 化疗，超过四分之一的局部肿瘤患者和几乎所有转移患者 在最初的临床缓解后，疾病将在遥远的部位复发。不幸的是，这些产品的前景 患者令人沮丧，迫切需要新的治疗方法。最大的障碍之一 改善EFT患者预后和生活质量的关键是我们无法预测谁有患EFT的风险 转移复发，并有效地确定和定位这一过程的基础机制。这个 这项提案中概述的研究旨在解决我们知识中的这些关键差距。 我们的总体目标是通过防止转移性复发来改善EFT患者的预后。在一次努力中 为了实现这一目标，我们将解决三个具体目标。首先，我们将使用细胞系的研究来评估 CXCR4阳性EFT细胞在介导EFT转移中的作用我们还将确定是否入侵 CXCR4的下游受RhoA的调节和依赖。第二，我们将测试小分子 体外、体内外RhoA/MKL转录轴抑制剂作为新型药物的疗效评价 用于预防EFT转移的药物。第三，我们将使用回溯性和前瞻性收集的 EFT样本验证G蛋白偶联受体表达是否可用于预测高危 新诊断患者中的疾病。演示CXCR4、CXCR7和/或LGR5表达式可以 用于识别有高转移复发风险的患者将允许将患者分类为临床风险 类别。反过来，这将允许治疗分层和确定哪些患者应该 包括在未来旨在防止高危患者复发的试验中。

Ewing sarcoma family tumors (EFT) are highly malignant bone and soft tissue tumors that primarily affect children, adolescents and young adults. Despite aggressive local control measures and systemic chemotherapy, over a quarter of patients with localized tumors and nearly all patients with metastatic disease will relapse at distant sites following initial clinical remission. Unfortunately, the outlook for these patients is dismal and novel approaches to therapy are desperately needed. One ofthe biggest impediments to improving outcomes and quality of life for patients with EFT is our inability to predict who is at risk for metastatic relapse and to effectively identify and target the mechanisms that underlie this process. The studies outlined in this proposal aim to address these critical gaps in our knowledge. It is our overall goal to improve outcomes for patients with EFT by preventing metastatic relapse. In an effort to achieve this goal we will address three specific aims. First, we will use studies of cell lines to evaluate the role of CXCR4 positive EFT cells in mediating EFT metastasis. We will also determine if invasion downstream of CXCR4 is mediated by and dependent on RhoA. Second, we will test small molecule inhibitors of the RhoA/MKL transcriptional axis in vitro, ex vivo and in vivo to evaluate their efficacy as novel agents forthe prevention of EFT metastasis. Third, we will use retrospectively and prospectively collected EFT samples to validate whether expression of G-protein coupled receptors can be used to predict high-risk disease in newly diagnosed patients. Demonstration that CXCR4, CXCR7 and/or LGR5 expression can be used to identify patients at high risk of metastatic relapse will allow classification of patients into clinical risk categories. In turn, this will allow for treatment stratification and identification of patients who should be included in future trials that are designed to prevent relapse in high-risk patients.