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，并且已经证明（i）PDGFR在转移性髓母细胞瘤中显着过度表达，（ii）髓母细胞瘤细胞PDGFR活性的抑制剂降低下游信号传导靶标MAPK的磷酸化， 改变基因表达，并减少细胞迁移和存活；(iii)对髓母细胞瘤的微阵列基因表达的独立数据集中的135个已知促转移基因进行计算机分析，只有包括DDGFR在内的三个基因在至少三分之一的分析肿瘤中显示出可检测到的mRNA表达，并且在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，显示受体的α (PDGFRA) 和β (PDGFRB) 亚型1) 在髓母细胞瘤肿瘤和细胞的RNA和蛋白质水平上表达，2) 在正常脑中稀疏表达，3) 在髓母细胞瘤细胞中以自分泌和旁分泌方式激活，4) 能够诱导髓母细胞瘤细胞凋亡 用 PDGFR 酪氨酸激酶活性的选择性抑制剂治疗后，髓母细胞瘤细胞以剂量依赖的方式进行研究，这表明 PDGFR 可能对髓母细胞瘤的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 信号级联反应及其对生存、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 特异的诱导 siRNA 转染来开发具有缺陷 PDGFR 表达的髓母细胞瘤细胞，并确定抑制表达和活性对细胞的影响。 体外存活、增殖和迁移以及体内生长和转移，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 抑制剂对该疾病的潜在临床效用的一种方法