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

研究 G 蛋白偶联受体 (GPCR) 作为攻击性生物标志物

• 批准号: 8395390
• 负责人: Elizabeth R Lawlor
• 金额: $ 26.3万
• 依托单位: SARC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395390
• 关键词: Actins; Address; Adolescent; Affect; Apoptosis; Archives; Biochemical; Biological Assay; Biological Markers; Biopsy; Bone Tissue; CXCR4 gene; Categories; Cell Death; Cell Line; Cell Proliferation; Cells; Child; Children' s Oncology Group; Classification; Clinical; Clinical Trials; Clinical Trials Design; Computer Simulation; Coupled; Cytoskeleton; Cytotoxic agent; Data; Diagnosis; Disease; Distant; Dose-Limiting; Drug Design; Drug Exposure; Drug resistance; Engraftment; Ewings sarcoma; Exposure to; Family; Future; G-Protein-Coupled Receptors; Gene Expression; Genetic Transcription; Goals; Growth; In Vitro; Institution; Knowledge; Lead; Malignant - descriptor; Measures; Mediating; Mediator of activation protein; Minority; Neoplasm Metastasis; Newly Diagnosed; Nuclear; Nuclear Translocation; Outcome; Pathway interactions; Patients; Phase; Phenotype; Population; Prevention; Process; Proteins; Publishing; Quality of life; RNA; Recurrence; Regimen; Relapse; Risk; Role; Sampling; Site; Soft Tissue Neoplasms; Sorting - Cell Movement; Specimen; Stem cells; Stratification; Testing; Time; Toxic effect; Tumor Cell Invasion; Tumor Cell Line; analog; base; cancer stem cell; cell motility; cellular engineering; chemokine receptor; chemotherapy; clinical remission; cytotoxic; disorder later incidence prevention; efficacy testing; gamma-Chemokines; high risk; improved; in vivo; inhibitor/antagonist; migration; neoplastic cell; novel; novel strategies; preclinical study; prevent; prognostic; rho; sarcoma; small molecule; treatment strategy; tumor; young adult

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.

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、青少年和年轻人。尽管采取了积极的地方控制措施和系统性措施 化疗，超过四分之一的患者患有局部肿瘤，几乎所有患者患有转移性肿瘤 初始临床缓解后，疾病将在远处复发。不幸的是，这些的前景 患者情绪低落，迫切需要新的治疗方法。最大的障碍之一 为了改善 EFT 患者的治疗结果和生活质量，我们无法预测谁有患 EFT 的风险 转移复发并有效识别和针对这一过程的机制。这 本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预防转移复发来改善 EFT 患者的预后。在努力中 为了实现这一目标，我们将实现三个具体目标。首先，我们将利用细胞系研究来评估 CXCR4 阳性 EFT 细胞在介导 EFT 转移中的作用。我们还将确定是否有入侵 CXCR4 的下游由 RhoA 介导并依赖于 RhoA。其次，我们将测试小分子 体外、离体和体内 RhoA/MKL 转录轴抑制剂，以评估其新颖的功效 预防EFT转移的药物。第三，我们将使用回顾性和前瞻性收集的 EFT 样本验证 G 蛋白偶联受体的表达是否可用于预测高风险 新诊断患者的疾病。证明 CXCR4、CXCR7 和/或 LGR5 表达可以 用于识别转移复发高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识别应该接受治疗的患者 包括在未来旨在预防高危患者复发的试验中。