CCL2 and CCR2 as metastatic drivers and therapeutic targets in medulloblastoma

CCL2 和 CCR2 作为髓母细胞瘤的转移驱动因素和治疗靶点

• 批准号: 10320941
• 负责人: Livia Garzia
• 金额: $ 77.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320941
• 关键词: Antibodies; Attenuated; Binding; Biological Markers; Blocking Antibodies; Blood; Blood Circulation; Brain; Brain Neoplasms; CCL2 gene; Cancer Etiology; Carcinoma; Cause of Death; Cells; Cellular biology; Cerebrospinal Fluid; Cessation of life; Child; Childhood; Childhood Malignant Brain Tumor; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Disease; Disease Progression; Distal; Excision; FDA approved; Genes; Genetic; Hematogenous; Hematogenous Spread; Homing; Human; Image; Individual; Inflammatory; Left; Leptomeninges; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Membrane; Metastatic to; Modeling; Morbidity - disease rate; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nervous system structure; Neuraxis; Nonmetastatic; Organ; Patients; Pattern; Pharmaceutical Preparations; Play; Prevention; Primary Neoplasm; Publications; Radiation; Recurrence; Role; SHH gene; Seeds; Series; Solid; Solid Neoplasm; Source; Spinal Cord; Subgroup; Surface; Survival Rate; Survivors; Techniques; Xenograft procedure; biomarker development; chemokine; chemotherapy; childhood cancer mortality; cognitive disability; disability; economic cost; efficacy evaluation; experience; experimental study; implantation; improved; in vivo; knock-down; macrophage; medulloblastoma; monocyte chemoattractant protein 1 receptor; mouse model; neoplastic cell; novel diagnostics; novel strategies; novel therapeutics; overexpression; paracrine; patient derived xenograft model; physically handicapped; pre-clinical; prevent; prophylactic; social; targeted agent; targeted treatment; therapeutic target; therapy development; tool; transcriptome; tumor

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.

项目概要 脑肿瘤是最常见的实体瘤，也是儿童癌症相关死亡的主要原因。 髓母细胞瘤（MB）是最常见的恶性儿童脑肿瘤。 MB 的播散（转移） 导致覆盖大脑和脊髓的软脑膜被播种。独特的图案 传播导致了一个相对非经验支持的模型，其中髓母细胞瘤被认为是 通过细胞被动脱落到脑脊液中传播，然后远端植入 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 就像所有其他已知类型的人类癌症一样，通过血液循环传播 血行播散的循环肿瘤细胞（CTC）重新归巢至软脑膜室 神经系统。 CTC 几乎完全在软脑膜上重新播种，很少在软脑膜之外播种器官。 中枢神经系统。髓母细胞瘤的血行播散是一项令人兴奋的发展，它提供了 寻找诊断、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就诊前进行影像学检查时会经历“无转移”期。 转移复发，这可能提供预防转移复发的窗口。在已确诊的患者中 转移性疾病，识别 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新的诊断和治疗机会。因此我们 将要： 目标1）。使用 MB 分离并分析人类和小鼠的循环肿瘤细胞，以确定其效用 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 表达以确定贡献 人类异种移植和基因改造小鼠模型中的每种MB转移都概括了不同的 MB亚组。 目标3）。使用 FDA 批准的既定药物和抗体，以及新兴药物和工具化合物， 单独、共同或与化疗和颅脊髓放疗联合阻断 CCL2/CCR2 在小鼠模型中，以确定我们是否可以在临床前预防和/或治疗 MB 的传播。 尽管转移是髓母细胞瘤转移的主要治疗手段，但目前还没有针对髓母细胞瘤转移的药物或疗法。 压倒性的死亡原因，也是长期发病的主要来源。我们提出了一系列实验 阐明脑肿瘤如何血行扩散，识别标记物以改进诊断，并开发 近期适用于治疗儿童转移性MB的疗法。