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

定义和靶向中枢神经系统软脑膜转移的新途径

基本信息

批准号：
9888134
负责人：
Dorothy A Sipkins
金额：
$ 36.73万
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/9888134
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 Modeling 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 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.

抽象的癌症转移到软脑膜 (LM) 很难治疗，会产生显着的发病率，并且预测生存率极低，目前尚无预防 LM 疾病的分子靶向方法。 LM 转移常见于血液系统恶性肿瘤，例如急性淋巴细胞白血病。（ALL），并且实体瘤的发病率正在上升，我们最近报道了一种新的机制，即 ALL 细胞。通过沿导血的腔外表面迁移而侵入中枢神经系统 (CNS) LM 连接椎骨和颅骨骨髓的血管和蛛网膜下腔的所有细胞都劫持了a。涉及α6整合素受体和层粘连蛋白结合的神经干细胞发育迁移途径相互作用，以便沿着这种独特的脉管系统富含层粘连蛋白的基底膜爬行。血管从骨髓穿过椎骨或颅骨的孔直接进入 LM。表达层粘连蛋白受体α6的恶性细胞沿着该桥接的外表面侵入。以整合素依赖的方式绕过血管系统，绕过外周循环和血脑屏障有效地转移到 LM 这一发现解释了 LM 频繁转移的临床观察结果。发生在没有脑实质疾病参与的情况下。在本提案中，我们将定义信号传导。 α6 整合素-层粘连蛋白结合后在白血病细胞中激活的事件，决定了 α6 的作用整合素-层粘连蛋白在乳腺癌软脑膜转移中的相互作用，并测试下游的功效这些研究在 ALL 和乳腺癌 LM 转移的小鼠模型中通过抑制 PI3K 来靶向该通路。将为人们了解甚少的生物现象和治疗方法提供新的机制见解到临床需求高度未满足的领域。