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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

尤因肉瘤家族肿瘤（EFT）是高度恶性的骨骼和软组织肿瘤，主要影响儿童，青少年和年轻人。尽管有积极的地方控制措施和全身性化学疗法，超过四分之一的局部肿瘤患者，几乎所有转移性患者初始临床缓解后，疾病将在遥远部位复发。不幸的是，这些前景患者是惨淡的，迫切需要新颖的治疗方法。最大的障碍之一为了改善EFT患者的结局和生活质量是我们无法预测谁有的风险转移性复发，并有效识别和针对该过程的基础的机制。这该提案中概述的研究旨在解决我们知识中的这些关键差距。通过预防转移性复发来改善EFT患者的结果是我们的总体目标。努力为了实现这一目标，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的下游是由RhoA介导的，并取决于Rhoa。其次，我们将测试小分子 RhoA/Mkl转录轴的抑制剂在体外，离体和体内抑制剂，以评估其作为新颖的疗效预防EFT转移的代理。第三，我们将追溯和前瞻性地使用 EFT样品以验证是否可以使用G蛋白偶联受体的表达来预测高风险新诊断的患者的疾病。证明CXCR4，CXCR7和/或LGR5表达可以是用于识别具有转移性复发高风险的患者将使患者分类为临床风险类别。反过来，这将允许治疗分层和鉴定应为包括在未来的试验中，旨在防止高危患者复发。