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Defining and targeting a novel pathway for central nervous system leptomeningeal metastasis

定义和针对中枢神经系统软脑膜转移的新途径

基本信息

批准号：
10553654
负责人：
Dorothy A Sipkins
金额：
$ 34.94万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-06 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10553654
关键词：
Acute Lymphocytic Leukemia Antibodies Area Automobile Driving Basement membrane Binding Biological Phenomena Biology Blood - brain barrier anatomy Blood Vessels Bone Marrow Bone Surface Brain Breast Cancer Cell Breast Cancer cell line Bypass Calvaria Cell Line Cell surface Cells Central Nervous System Central Nervous System Diseases Circulation Clinical Clinical Data Complex Complication Data Development Diagnosis Disease Disseminated Malignant Neoplasm Estrogen receptor positive Event Extracellular Matrix FDA approved Frequencies Hematologic Neoplasms Human In Vitro Incidence Individual Integrin alpha6 Integrins Intervention Intrathecal Chemotherapy Invaded Laboratories Laminin Laminin Receptor Leptomeningeal Neoplasms Leptomeninges Leukemic Cell Malignant neoplasm of lung Meningeal Metastatic Neoplasm to the Central Nervous System Metastatic Neoplasm to the Leptomeninges Metastatic malignant neoplasm to brain Molecular Molecular Target Morbidity - disease rate Mus Neoplasm Metastasis Neurons PIK3CG gene Pathway interactions Patients Peripheral Pre-Clinical Model Prognostic Marker Prophylactic treatment Recurrent disease Relapse Reporting Role Sampling Signal Transduction Solid Neoplasm Specimen Subarachnoid Space Surface Therapeutic Work Xenograft Model Xenograft procedure acute lymphoblastic leukemia cell bone cancer cell cancer subtypes cell motility design diagnostic tool efficacy testing genetically modified cells high risk in vivo inhibitor insight leukemia malignant breast neoplasm migration molecular targeted therapies mouse model nerve stem cell neural novel novel therapeutics patient derived xenograft model preclinical study prevent prophylactic receptor spine bone structure stem stem cells translational study triple-negative invasive breast carcinoma tumor

项目摘要

ABSTRACT Cancer metastases to the leptomeninges (LM) are difficult to treat, create significant morbidity, and predict extremely poor survival. There are currently no molecularly targeted approaches to prevent LM disease involvement. LM metastases are frequent in hematologic malignancies such as acute lymphoblastic leukemia (ALL), and the incidence in solid tumors is rising. We recently reported a novel mechanism whereby ALL cells invade the central nervous system (CNS) LM by migrating along the abluminal surface of emissary blood vessels that bridge the vertebral and calvarial bone marrow and subarachnoid spaces. ALL cells hijack a neural stem cell developmental migration pathway involving α6 integrin receptor and laminin binding interactions in order to crawl along the laminin-rich basement membrane of this unique vasculature. These vessels pass from the bone marrow through apertures in the vertebral or calvarial bone to directly enter the LM. Malignant cells expressing the laminin receptor, α6, invade along the external surface of this bridging vasculature in an integrin-dependent fashion, bypassing the peripheral circulation and the blood brain barrier to efficiently metastasize to the LM. This finding explains the clinical observation that LM metastases frequently occur in the absence of brain parenchymal disease involvement. In this proposal, we will define the signaling events that are activated in leukemic cells upon α6 integrin-laminin engagement, determine the role of α6 integrin-laminin interactions in breast cancer leptomeningeal metastasis, and test the efficacy of downstream PI3K inhibition to target this pathway in mouse models of ALL and breast cancer LM metastasis. These studies will provide new mechanistic insight into a poorly understood biologic phenomenon and a therapeutic approach to an area of high unmet clinical need.

摘要