CCL2 and CCR2 as metastatic drivers and therapeutic targets in medulloblastoma

项目总结 脑瘤是最常见的实体肿瘤，也是儿童癌症相关死亡的主要原因。 髓母细胞瘤(MB)是儿童最常见的恶性脑肿瘤。甲基溴的传播(转移) 结果种植覆盖大脑和脊髓的软脑膜。独一无二的模式 扩散导致了一个相对非经验性的模型，在该模型中，髓母细胞瘤被假设为 通过被动地将细胞脱落到脑脊液中传播，然后在远端植入 神经系统的表面。我们现在已经通过实验证明，髓母细胞瘤实际上 就像所有其他已知的人类癌症一样，通过血液循环传播， 血源性播散性循环肿瘤细胞(CTCs)向软脑膜室的重新归巢 神经系统。CTC几乎完全重新种植软脑膜，很少种植外部器官。 中枢神经系统。髓母细胞瘤的血源性播散是一个令人兴奋的发展，它提供了 诊断、预防和治疗转移性髓母细胞瘤的新方法的机会。 绝大多数髓母细胞瘤患者在接受治疗前都会经历一段“无转移”的间期。 转移复发，这可能为预防转移复发提供一个窗口。在已确定的患者中 转移性疾病，识别使CTC驱动转移的基因可以预防或改善疾病 进展，为髓母细胞瘤患者提供了新的诊断和治疗机会。因此我们 将： 目标1)。分离和分析MB感染的人和小鼠的循环肿瘤细胞以确定其应用价值 CCL2和CCR2作为不同MB亚组内转移发展的生物标志物。 目标2)。使用遗传/细胞生物学技术操纵CCL2/CCR2的表达以确定其贡献 在人类异种移植和转基因小鼠模型中对MB转移的每一个都概括了不同的 MB子组。 目标3)。使用FDA批准的现有药物和抗体，以及新兴药物和工具化合物， 阻断CCL2/CCR2，单独、联合及联合化疗和脊髓放疗 在小鼠模型中，以确定我们是否可以预防和/或治疗临床前MB的传播。 目前还没有治疗髓母细胞瘤转移的药物或疗法，尽管转移是 压倒性的死亡原因，也是长期发病率的主要来源。我们提出了一系列实验 阐明了脑瘤是如何通过血液传播的，识别标志物以提高诊断和发展 近期适用于治疗儿童转移性MB的治疗方法。

PROJECT SUMMARY Brain tumors are the most common solid tumor and the leading cause of cancer-related death in children. Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dissemination (metastasis) of MB results in seeding the leptomeningeal membranes that cover the brain and spinal cord. The unique pattern of dissemination leads to a relatively non-empirically supported model in which medulloblastoma was assumed to spread through passive shedding of cells into the cerebrospinal fluid, followed by distal implantation on the surface of the nervous system. We have now demonstrated experimentally, that medulloblastoma in fact disseminates through the blood circulation just like every other known type of human cancer, with hematogenously disseminated circulating tumor cells (CTCs) re-homing to the leptomeningeal compartment of the nervous system. CTCs reseed the leptomeninges almost exclusively, only rarely seeding organs outside the central nervous system. Hematogenous dissemination of medulloblastoma is an exciting development that offers the chance for novel approaches to the diagnosis, prevention, and treatment of metastatic medulloblastoma. The vast majority of medulloblastoma patients experience a `metastasis free' interval by imaging before their metastatic recurrence, which may offer a window to prevent metastatic recurrence. In patients with established metastatic disease, identifying the genes enabling CTCs to drive metastases could prevent or ameliorate disease progression, offering novel diagnostic and therapeutic opportunities for medulloblastoma patients. Therefore we will: Aim 1). Isolate and analyze circulating tumor cells from humans and mice with MB to determine the utility of CCL2 and CCR2 as biomarkers for the development of metastases within distinct MB subgroups. Aim 2). Manipulate CCL2/CCR2 expression using genetic/cell biology techniques to determine the contribution of each to MB metastasis in human xenograft and genetically modified mouse models that recapitulate distinct MB subgroups. Aim 3). Use established FDA approved drugs and antibodies, as well as emerging drugs and tool compounds, to block CCL2/CCR2, individually, together, and in combination with chemotherapy and craniospinal radiation in mouse models, to determine if we can prevent, and/or treat the dissemination of MB preclinically. There are no drugs or therapies for medulloblastoma metastases, despite the fact that metastases are the overwhelming cause of death, and the major source of long-term morbidity. We present a series of experiments that clarify how brain tumors can spread hematogenously, identify markers to improve diagnosis, and develop therapies applicable in near term to the treatment of metastatic MB in children.