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

摘要 癌症转移到软脑膜（LM）是难以治疗的，产生显著的发病率， 生存率极低目前还没有分子靶向方法来预防LM疾病 参与。LM转移是常见的血液恶性肿瘤，如急性淋巴细胞白血病 (ALL)在实体瘤中的发病率正在上升。我们最近报道了一种新的机制， 通过沿着导血腔外表面迁移侵入中枢神经系统（CNS）LM 桥接脊椎和颅骨骨髓和蛛网膜下腔的血管。所有细胞劫持一个 神经干细胞发育迁移途径与α6整合素受体和层粘连蛋白的结合 相互作用，以便沿着沿着这种独特的脉管系统的富含层粘连蛋白的基底膜爬行。这些 血管从骨髓穿过脊椎骨或颅骨中的孔 LM。表达层粘连蛋白受体α6的恶性细胞沿着这个桥的外表面侵入 以整合素依赖的方式，绕过外周循环和血脑屏障， 有效转移到LM。这一发现解释了临床观察，LM转移频繁， 发生在没有脑实质疾病累及的情况下。在本提案中，我们将定义信令 白血病细胞中α6整合素-层粘连蛋白结合后激活的事件，决定了α6整合素的作用。 整合素-层粘连蛋白在乳腺癌软脑膜转移中的相互作用，并测试下游整合素的疗效。 PI 3 K抑制在ALL和乳腺癌LM转移的小鼠模型中靶向该通路。这些研究 将提供新的机制深入了解一个鲜为人知的生物现象和治疗方法 一个高度未满足的临床需求领域。

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.