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肿瘤，也是儿童癌症相关死亡的主要原因。 髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。MB扩散（转移） 导致覆盖大脑和脊髓的软脑膜接种。的唯一模式 传播导致一个相对非经验支持的模型，其中髓母细胞瘤被假定为 通过细胞被动脱落扩散到脑脊液中，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， 造血播散的循环肿瘤细胞（CTC）重新归巢到软脑膜隔室， 神经系统CTC几乎只在软脑膜上播种，很少在软脑膜外播种器官。 中枢神经系统髓母细胞瘤的血行播散是一个令人兴奋的发展， 转移性髓母细胞瘤的诊断、预防和治疗的新方法的机会。 绝大多数髓母细胞瘤患者在其治疗前通过成像经历“无转移”间隔， 转移复发，这可能提供了一个窗口，以防止转移复发。在已确诊的 转移性疾病，识别能够使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新的诊断和治疗机会。因此我们 将： 目标1）。分离和分析来自患有MB的人类和小鼠的循环肿瘤细胞，以确定 CCL 2和CCR 2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CCL 2/CCR 2表达，以确定CCL 2/CCR 2表达的贡献。 在人类异种移植物和遗传修饰的小鼠模型中， MB亚组。 目标3）。使用FDA批准的药物和抗体，以及新兴药物和工具化合物， 阻断CCL 2/CCR 2，单独、联合以及联合化疗和颅脊髓放射治疗 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。 尽管髓母细胞瘤的转移是肿瘤的主要原因， 这是造成死亡的主要原因，也是长期发病的主要原因。我们提出了一系列的实验 阐明了脑肿瘤如何通过造血途径扩散，识别标志物以改善诊断， 近期适用于治疗儿童转移性MB的疗法。