Overcoming Leukemia Chemoresistance in the Central Nervous System

克服中枢神经系统的白血病化疗耐药性

基本信息

批准号：
10357911
负责人：
PETER M GORDON
金额：
$ 35.23万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2020-03-04 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10357911
关键词：
AMD3100 Acute Lymphocytic Leukemia Adhesions Antibodies Apoptosis Apoptotic Attenuated Biological Assay Biological Models Biology Blood Blood - brain barrier anatomy Bone Marrow CXCR4 gene Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Line Cell Surface Proteins Cell Survival Cells Central Nervous System Leukemia Cerebrospinal Fluid Chemoresistance Child Clinic Clinical Trials Coculture Techniques Cytarabine Data Equilibrium Exhibits FDA approved Genetic Hematopoietic stem cells Homo In Vitro Knowledge Leukemic Cell Link Mediating Meningeal Meninges Molecular Morbidity - disease rate Mus Neuraxis Outcome Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacology Proteomics Public Health Quality of life Regulation Relapse Research Role Serum Signal Pathway System Testing Therapeutic Toxic effect Translating Treatment Efficacy Treatment Failure Up-Regulation Work Xenograft procedure antagonist base chemotherapy clinically translatable improved in vivo in vivo Model in vivo evaluation insight knock-down leukemia leukemia relapse new therapeutic target novel novel strategies novel therapeutic intervention prevent small hairpin RNA small molecule supportive environment therapeutic evaluation

项目摘要

ABSTRACT Central nervous system (CNS) relapse is a major cause of treatment failure among patients with acute lymphoblastic leukemia (ALL). Notably, isolated CNS relapse occurs in ~3-8% of children with ALL and accounts for 30–40% of initial relapses in some clinical trials. Furthermore, current CNS-directed therapies are associated with significant toxicities. As a result, novel CNS-directed leukemia therapies are urgently needed to improve long-term outcomes while decreasing treatment-related morbidity. Although extensive research has demonstrated a critical role of the bone marrow microenvironment in leukemia biology, the impact of the CNS microenvironment on leukemia cell survival and chemoresistance is largely unknown. We developed a novel ex vivo co-culture system and an in vivo xenotransplantation approach to investigate the effects of the CNS niche on leukemia biology and chemoresistance. We then used these model systems to identify that 1) leukemia cells cultured in cerebral spinal fluid (CSF) in vitro and in vivo have diminished survival relative to serum or media, 2) leukemia cells predominantly localize to the meninges within the CNS, and 3) leukemia cells co-cultured with meningeal cells, or associated with the meninges of mice, exhibit enhanced survival and chemoresistance. We then identified that direct meningeal-leukemia interactions promote leukemia cell survival by modulating apoptosis balance, cell cycle progression, and quiescence. Importantly, leukemia chemoresistance was reversible and overcome by detaching the leukemia cells from the meninges. We then used a co-culture adhesion assay to identify drugs that disrupt the interaction between leukemia and meningeal cells. In addition to identifying several drugs that inhibit canonical cell adhesion targets and pathways, including the CXCR4 antagonist AMD3100, we found that Me6TREN, a novel small-molecule hematopoietic stem cell (HSC) mobilizing compound, also disrupts the interaction between leukemia and meningeal cells. This work demonstrates that the meninges exert a unique and critical influence on leukemia chemoresistance and defines novel mechanisms of CNS relapse beyond the well-described role of the blood- brain barrier. Based on this work, our central hypothesis is that the leukemia-meningeal cell interaction is a critical regulator of leukemia cell survival and chemoresistance in the CNS. Moreover, from a therapeutic standpoint, we hypothesize that niche disruption may be more efficacious in the CNS than in the bone marrow because of the less supportive environment of the CSF relative to the blood or serum. The objectives in this proposal are to use our in vitro and in vivo model systems for CNS leukemia to dissect the molecular mechanisms that mediate leukemia adhesion (Aim 1) and chemoresistance (Aim 2) in the CNS and test novel, clinically translatable therapies for CNS leukemia including Me6TREN and AMD3100 (Aim 3). !

抽象的中枢神经系统（CNS）复发是急性重症患者治疗失败的主要原因值得注意的是，约 3-8% 的 ALL 儿童会出现孤立性中枢神经系统复发。在一些临床试验中，这种情况占初次复发的 30-40%。此外，目前的 CNS 导向疗法是因此，迫切需要新的针对中枢神经系统的白血病疗法。改善长期结果，同时降低治疗相关的发病率。骨髓微环境在白血病生物学中的关键作用，中枢神经系统的影响微环境对白血病细胞存活和化疗耐药性的影响在很大程度上是未知的。离体共培养系统和体内异种移植方法研究中枢神经系统的影响然后我们使用这些模型系统来识别白血病生物学和化疗耐药性的利基市场 1) 体外和体内在脑脊液（CSF）中培养的白血病细胞的存活率相对于血清或培养基，2) 白血病细胞主要定位于中枢神经系统内的脑膜，以及 3) 白血病与脑膜细胞共培养或与小鼠脑膜相关的细胞表现出更高的存活率和然后我们发现脑膜-白血病的直接相互作用可促进白血病细胞的存活。通过调节细胞凋亡平衡、细胞周期进程和静止，重要的是，白血病。然后，我们将白血病细胞从脑膜上分离出来，从而克服了化学耐药性。使用共培养粘附测定来识别破坏白血病和白血病之间相互作用的药物除了确定几种抑制典型细胞粘附靶标的药物外，途径，包括 CXCR4 拮抗剂 AMD3100，我们发现 Me6TREN，一种新型小分子造血干细胞 (HSC) 动员化合物，也会破坏白血病和白血病之间的相互作用这项工作表明脑膜对白血病具有独特而关键的影响。化学耐药性并定义了中枢神经系统复发的新机制，超越了血液的良好描述的作用基于这项工作，我们的中心假设是白血病-脑膜细胞相互作用是一种此外，中枢神经系统中白血病细胞存活和化疗耐药性的关键调节剂。站起来，我们承认生态位破坏可能在中枢神经系统中比在骨髓中更有效因为相对 CSF 对血液或血清的支持环境较差。建议使用我们的 CNS 白血病体外和体内模型系统来剖析分子介导中枢神经系统中白血病粘附（目标 1）和化疗耐药（目标 2）的机制并测试新颖， CNS 白血病的临床可转化疗法包括 Me6TREN 和 AMD3100（目标 3）。！