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.
Medulloblastoma is the most common malignant pediatric brain tumor, with deaths occurring due to metastatic spread of primary tumor to the leptomeningeal membranes that cover the brain and spinal cord. We present data that these metastases actually arise through active hematogenous dissemination rather than via passive spread through the CSF, as was presumed. We outline aims to determine the role of hematogenous dissemination across MB subgroups; determine the preclinical utility of circulating tumors cellsas a biomarker for metastasis; and to clarify roles and therapies for CCL2 and CCR2 in metastases.
