The Role of PDGFR in Medulloblastoma Progression

PDGFR 在髓母细胞瘤进展中的作用

• 批准号: 7095792
• 负责人: TOBEY J. MACDONALD
• 金额: $ 26.52万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095792
• 关键词: medulloblastoma; neoplasm /cancer; role

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children. To approach the problem of effective therapy, the progression of human medulloblastoma must first be understood. We hypothesize that platelet-derived growth factor (PDGFR)-mediated signal transduction enhances tumor cell responses that promote the growth and metastatic spread of medulloblastoma, and have shown that (i) PDGFR is significantly overexpressed by metastatic medulloblastomas, (ii) inhibitors of medulloblastoma cell PDGFR activity decrease phosphorylation of the downstream signaling target, MAPK, alter gene expression, and decrease cell migration and survival and (iii) in silico analysis of 135 known pro-metastatic genes within independent datasets of microarray gene expression of medulloblastomas, only three genes, including DDGFR, demonstrated detectable mRNA expression in at least one third of all tumors analyzed and significant overexpression by metastatic tumors in each dataset. These data, combined with the preliminary data showing that both alpha (PDGFRA) and beta (PDGFRB) subtypes of the receptor are 1) expressed on the RNA and protein level by medulloblastoma tumors and cells, 2) sparsely expressed by normal brain, 3) activated in an autocrine and paracrine fashion in medulloblastoma cells, and 4) capable of inducing apoptosis of medulloblastoma cells in a dose-dependent manner following treatment with a selective inhibitor of PDGFR tyrosine kinase activity, suggest a mechanism by which PDGFR may be vital for medulloblastoma growth and progression. Thus, PDGFR is a potential novel target for therapeutic intervention. To test this hypothesis we will employ human medulloblastoma cell lines. We will (i) conduct comprehensive in vitro studies to determine the PDGFR signaling cascade and its effects on survival, proliferation, adhesion, migration and invasion, (ii) determine the key gene expression changes induced by PDGFR signaling in these cells, (iii) develop medulloblastoma cells with deficient PDGFR expression by inducible siRNA transfection specific for each PDGFR and determine the effect of inhibited expression and activity on survival, proliferation and migration in vitro and growth and metastasis in vivo, and (iv) determine the expression pattern of phosphorylated PDGFR protein and its correlation with metastasis and outcome in human medulloblastomas as a way to assess the potential clinical utility of PDGFR inhibitors for this disease

描述（由申请人提供）：髓母细胞瘤是儿童中最常见的恶性脑肿瘤。为了解决有效治疗的问题，必须首先了解人类髓母细胞瘤的进展。我们假设血小板源性生长因子 (PDGFR) 介导的信号转导增强肿瘤细胞反应，从而促进髓母细胞瘤的生长和转移性扩散，并表明 (i) PDGFR 在转移性髓母细胞瘤中显着过度表达，(ii) 髓母细胞瘤抑制剂细胞 PDGFR 活性降低下游信号传导靶标 MAPK 的磷酸化，改变基因表达，并降低细胞迁移和存活率，以及 (iii) 计算机模拟分析髓母细胞瘤微阵列基因表达的独立数据集中有 135 个已知的促转移基因，只有 3 个基因（包括 DDGFR）在至少三分之一的分析肿瘤中表现出可检测到的 mRNA 表达，并且每个数据集中转移性肿瘤显着过度表达。这些数据与初步数据相结合，表明受体的 α (PDGFRA) 和 β (PDGFRB) 亚型 1) 在髓母细胞瘤和细胞的 RNA 和蛋白质水平上表达，2) 在正常大脑中稀疏表达，3)在髓母细胞瘤细胞中以自分泌和旁分泌方式激活，并且4)在用选择性抑制剂治疗后能够以剂量依赖性方式诱导髓母细胞瘤细胞凋亡PDGFR 酪氨酸激酶活性表明 PDGFR 可能对髓母细胞瘤生长和进展至关重要。因此，PDGFR 是治疗干预的潜在新靶点。为了检验这一假设，我们将采用人髓母细胞瘤细胞系。我们将 (i) 进行全面的体外研究，以确定 PDGFR 信号级联及其对生存、增殖、粘附、迁移和侵袭的影响，(ii) 确定这些细胞中 PDGFR 信号传导诱导的关键基因表达变化，(iii)通过对每种 PDGFR 特异性的诱导型 siRNA 转染来培养 PDGFR 表达缺陷的髓母细胞瘤细胞，并确定受抑制的表达和活性对体外存活、增殖和迁移以及体内生长和转移的影响，以及 (iv) 确定磷酸化 PDGFR 蛋白的表达模式及其与人髓母细胞瘤转移和结果的相关性，作为评估 PDGFR 抑制剂治疗该疾病的潜在临床效用的方法