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.

项目摘要 脑肿瘤是最常见的实体瘤，也是儿童与癌症相关死亡的主要原因。 髓母细胞瘤（MB）是最常见的恶性小儿脑肿瘤。 MB的传播（转移） 导致播种覆盖大脑和脊髓的瘦脑膜。独特的模式 传播导致一个相对非经验支持的模型，其中假定髓母细胞瘤为 通过细胞的被动脱落进入脑脊液，然后在远端植入脑脊液中传播 神经系统的表面。我们现在已经通过实验证明了髓母细胞瘤实际上 像其他所有已知类型的人类癌症一样，通过血液循环传播 血源性传播的循环肿瘤细胞（CTC）将其归为瘦脑室 神经系统。 CTC几乎完全恢复了瘦素，只有很少在外面播种器官 中枢神经系统。髓母细胞瘤的血源性传播是一种令人兴奋的发展，可提供 新型方法进行转移性髓母细胞瘤的诊断，预防和治疗的机会。 绝大多数髓母细胞瘤患者在成像之前会经历“无转移”间隔 转移性复发，这可能提供一个窗口，以防止转移性复发。在已建立的患者中 转移性疾病，识别使CTC驱动转移试剂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）。分离和分析使用MB的人和小鼠循环肿瘤细胞，以确定 CCL2和CCR2作为在不同MB亚组中发展转移的生物标志物。 目标2）。使用遗传/细胞生物学技术来操纵CCL2/CCR2表达以确定贡献 每个人异种移植物中的MB转移和转基因的小鼠模型，这些模型概括了不同 MB子组。 目标3）。使用已建立的FDA批准的药物和抗体，以及新兴药物和工具化合物， 单独，，，并结合化学疗法和颅脊髓辐射，阻止CCL2/CCR2 在小鼠模型中，确定我们是否可以预防和/或处理MB的传播。 尽管转移是髓母细胞瘤转移的药物或疗法 压倒性的死亡原因和长期发病的主要来源。我们提出了一系列实验 这阐明了脑肿瘤如何血源传播，识别标记以改善诊断并发展 适用于儿童转移性MB治疗的疗法。