Novel Strategies to Target Leukemia-Stromal Interactions

针对白血病-基质相互作用的新策略

• 批准号: 8825120
• 负责人: Peng Huang
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825120
• 关键词: Antioxidants; Apoptosis; Biochemical; Bone Marrow; Bone Marrow Cells; Cell Death; Cell Survival; Cells; Chemicals; Chronic Lymphocytic Leukemia; Clinical Treatment; Communication; Cysteine; Cystine; Dependency; Development; Drug resistance; Drug usage; Environment; Equilibrium; Europe; Exhibits; Generations; Genotype; Glutathione; Goals; Human; Immune; In Vitro; Indolent; Laboratories; Lead; Lymphocyte; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Nature; New Agents; Normal Cell; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Reactive Oxygen Species; Research; Research Project Grants; Role; Stromal Cells; System; Testing; Therapeutic; Time; Tissues; Toxic effect; United States; Xenograft procedure; adult leukemia; analog; base; design; differential expression; effective therapy; improved; in vivo; insight; killings; leukemia; mouse model; novel; novel strategies; novel therapeutics; oxidative damage; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Previous studies by our laboratory and others have showed that chronic lymphocytic leukemia (CLL) cells exhibit elevated ROS generation, and that this oxidative stress renders the leukemia cell highly dependent on cellular antioxidant systems such as glutathione (GSH) to maintain redox balance and cell viability. Our recent study further showed that CLL cells were highly dependent on the bone marrow stromal cells to alleviate oxidative stress and promote their survival and drug resistance through enhancing GSH synthesis mediated by an intercellular metabolic communication involving cystine cysteine conversion and shuttling between the two cell compartments. These research findings provide new mechanistic insights into the biochemical interaction between leukemia and stromal cells. Importantly, the dependency of CLL cells on stromal cells for redox balance and cell survival has revealed an Achilles heel of CLL cells that can be targeted for therapeutic purpose. The main goal of this research project is to test the hypothesis that the metabolic communication between bone marrow stromal cells and CLL cells in cystine/cysteine/GSH metabolism can be used as a novel mechanism to selectively kill the leukemia cells using agents that preferentially impact the leukemia cells in the stromal environment. We propose to investigate the three Specific Aims: (1) Develop a novel mechanism- based therapeutic strategy to utilize the stromal-CLL intercellular interaction in cystine cysteine GSH metabolism as a unique pathway to convert the cystine analogs to toxic metabolites capable of selectively killing leukemia cells in the stromal microenvironment. (2) Investigate the high therapeutic selectivity of the cystine analogs that preferentially targets CLL cells in the presence of stromal cells, and exam the underlying mechanisms. (3) Use several CLL mouse models to test the in vivo therapeutic activity of the novel agents that by hijacking the stromal-CLL intercellular metabolic pathway to effectively kill CLL cells in the stromal microenvironment in vivo. Significance: This study will significantly advance our understating of leukemia-stromal interaction at biochemical levels and the role of such intercellular metabolic communication in leukemia cell survival and drug resistance. This study will also lead to the development of novel therapeutic strategies to effectively kill CLL in stromal microenvironment in vivo. Currently there is no effective therapy to overcome CLL drug resistance caused by the protective stromal microenvironment. The propose study will fill this significant gap by developing a novel strategy to turns the protective stromal cells into a metabolic machinery that produces active metabolite to selectively kill leukemia cells in tissue microenvironment, and thus will have important therapeutic implications in clinical treatment of CLL patients.

描述（由申请人提供）：我们实验室和其他实验室的先前研究表明，慢性淋巴细胞白血病（CLL）细胞表现出ROS生成增加，并且这种氧化应激使白血病细胞高度依赖于细胞抗氧化系统，如谷胱甘肽（GSH），以维持氧化还原平衡和细胞活力。我们最近的研究进一步表明，CLL细胞高度依赖于骨髓基质细胞，以减轻氧化应激和促进其生存和耐药性，通过增强GSH合成介导的细胞间代谢通讯，涉及胱氨酸半胱氨酸转换和穿梭在两个细胞区室之间。这些研究结果为白血病和基质细胞之间的生化相互作用提供了新的机制见解。重要的是，CLL细胞对基质细胞的氧化还原平衡和细胞存活的依赖性揭示了CLL细胞的阿喀琉斯之踵，其可以被靶向用于治疗目的。本研究项目的主要目标是检验以下假设：骨髓基质细胞和CLL细胞之间在胱氨酸/半胱氨酸/GSH代谢中的代谢通讯可以用作一种新的机制，使用优先影响基质环境中白血病细胞的药物选择性杀死白血病细胞。我们提出研究三个具体目标：（1）开发一种新的基于机制的治疗策略，以利用胱氨酸半胱氨酸GSH代谢中的基质-CLL细胞间相互作用作为将胱氨酸类似物转化为能够选择性杀死基质微环境中白血病细胞的毒性代谢物的独特途径。(2)研究在基质细胞存在下优先靶向CLL细胞的胱氨酸类似物的高治疗选择性，并检查潜在的机制。(3)使用几种CLL小鼠模型来测试新型药剂的体内治疗活性，所述新型药剂通过劫持基质-CLL细胞间代谢途径来有效地杀死体内基质微环境中的CLL细胞。重要性：这项研究将显着推进我们的理解白血病间质的相互作用在生化水平和作用，这种细胞间的代谢通信白血病细胞的生存和耐药性。这项研究还将导致开发新的治疗策略，以有效地杀死CLL在体内基质微环境。目前还没有有效的治疗方法来克服由保护性基质微环境引起的CLL耐药性。该研究将通过开发一种新的策略来填补这一重大空白，将保护性基质细胞转化为代谢机制，产生活性代谢物以选择性地杀死组织微环境中的白血病细胞，从而在CLL患者的临床治疗中具有重要的治疗意义。