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

• 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
• 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

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）缓解是急性患者治疗失败的主要原因 淋巴细胞白血病（全部）。值得注意的是，孤立的中枢神经系统中继发生在约3-8％的全体儿童中 在一些临床试验中，占初始继电器的30–40％。此外，当前的CNS导向疗法是 与明显的毒性有关。结果，迫切需要新型的CNS指导性白血病疗法 改善长期结局，同时减少与治疗相关的发病率。尽管广泛的研究已经 表现出骨髓微环境在白血病生物学中的关键作用，CNS的影响 在白血病细胞存活和化学上的微环境基本上未知。我们开发了一本小说 离体共培养系统和一种体内异种移植方法研究中枢神经系统的影响 白血病生物学和化学抗性的利基市场。然后，我们使用这些模型系统来识别1） 在体外和体内培养在脑脊髓液（CSF）中的白血病细胞相对于生存率降低 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，3）白血病 与脑膜细胞共培养的细胞，或与小鼠脑膜相关的细胞，暴露了增强的生存率和 化学抗性。然后，我们确定直接脑膜白血病相互作用促进白血病细胞的存活 通过调节凋亡平衡，细胞周期进程和静止。重要的是，白血病 化学抗性是可逆的，并通过将白血病细胞与脑膜脱离来克服。然后我们 使用共培养的依从性测定来识别破坏白血病与 脑膜细胞。除了鉴定几种抑制规范细胞粘合剂靶标的药物和 途径，包括CXCR4拮抗剂AMD3100，我们发现Me6tren是一种新型的小分子 造血干细胞（HSC）动员化合物，也破坏了白血病与 脑膜细胞。这项工作表明，脑膜对白血病产生独特而关键的影响 化学抗性并定义了CNS继电器的新机制，超出了血液的描述性的作用。 脑屏障。基于这项工作，我们的中心假设是白血病含有细胞的相互作用是 中枢神经系统中白血病生存和化学抗性的关键调节剂。而且，从治疗性 角度，我们假设在中枢神经系统中的利基破坏可能比骨髓更有效 由于CSF相对于血液或血清的支持较少。其中的对象 建议是使用我们的体外和体内模型系统来剖析CNS白血病 中枢神经系统和测试小说中介导白血病广告（AIM 1）和化学耐药性（AIM 2）的机制， CNS白血病（包括ME6TREN和AMD3100）的临床翻译疗法（AIM 3）。 呢