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：
10079480
负责人：
Dorothy A Sipkins
金额：
$ 36.28万
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/10079480
关键词：
Acute Lymphocytic Leukemia Antibodies Area Automobile Driving Basement membrane Binding Biological Phenomena Biology Blood - brain barrier anatomy Blood Circulation Blood Vessels Bone Marrow Bone Surface Brain Breast Cancer Cell Breast Cancer cell line Bypass Calvaria Cell Line Cell surface Cells Central Nervous System Diseases Clinical Clinical Data Complex Complication Data Development Diagnosis Diagnostic Disease Disseminated Malignant Neoplasm Estrogen receptor positive Event Extracellular Matrix FDA approved Frequencies Hematologic Neoplasms Human In Vitro Incidence Individual Integrin alpha Chains Integrin alpha6 Integrins Intervention Intrathecal Chemotherapy Invaded Laboratories Laminin Laminin Receptor Leptomeningeal Neoplasms Leptomeninges Leukemic Cell Light 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 Neuraxis Neurons 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 base bone cancer cell cancer subtypes cell motility design efficacy testing genetically modified cells high risk in vivo inhibitor/antagonist insight leukemia malignant breast neoplasm migration molecular targeted therapies mouse model nerve stem cell novel novel therapeutics patient derived xenograft model preclinical study prevent prophylactic receptor relating to nervous system spine bone structure stem cells tool 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.

抽象的对钩烯酸（LM）的癌症转移很难治疗，产生明显的发病率，并且预测生存率极差。目前尚无分子靶向方法来预防LM疾病参与。 LM转移经常在血液学恶性肿瘤中，例如急性淋巴细胞白血病（全部），实体瘤的事件正在上升。我们最近报道了一种新型机制通过沿着紧急血液的排放表面迁移来入侵中枢神经系统（CNS）LM 弥合椎骨和钙骨髓骨髓和蛛网膜下腔空间的容器。所有牢房劫持A 神经干细胞发育迁移途径涉及α6整合素受体和层粘连蛋白结合相互作用是为了沿着这种独特的脉管系统的富含层粘连蛋白的地下膜爬行。这些血管通过椎骨或颅骨骨的孔从骨髓中传递出来，直接进入 LM。表达层粘连蛋白受体α6的恶性细胞沿着该桥梁的外表面侵入以整合素依赖性的方式进行脉管系统，绕过外围循环和血脑屏障有效地转移到LM。这一发现解释了LM转移经常的临床观察结果在此提案中，我们将定义信号在α6整合素 - 氯胺酮参与下在白血病细胞中激活的事件，确定α6的作用乳腺癌瘦脑脑转移中的整合素 - 氯胺酮相互作用，并测试下游的效率 PI3K抑制是针对所有小鼠模型和乳腺癌LM转移的途径。这些研究将为知识熟悉的生物学现象和治疗方法提供新的机械洞察力达到高未满足临床需求的领域。