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）：我们的实验室和其他人的先前研究表明，慢性淋巴细胞性白血病（CLL）细胞的产生升高，而这种氧化应激使白血病细胞高度依赖于细胞抗氧化剂系统，例如谷胱甘肽（GSH），以维持甲基丙烷（GSH），以维持氧化还原平衡和细胞平衡的能力。我们最近的研究进一步表明，CLL细胞高度依赖于骨髓间基质细胞，以减轻氧化应激，并通过增强涉及cySESTINE半胱氨酸转化和在两个细胞隔室之间穿梭的细胞质代谢通信介导的GSH合成，从而促进其存活和耐药性。这些研究发现为白血病和基质细胞之间的生化相互作用提供了新的机械见解。重要的是，CLL细胞对基质细胞对氧化还原平衡和细胞存活的依赖性揭示了CLL细胞的致命弱点，可以用于治疗目的。该研究项目的主要目的是检验假说，即胱氨酸/半胱氨酸/GSH代谢中骨髓基质细胞和CLL细胞之间的代谢通信可以用作一种新型机制，可以选择性地杀死白血病细胞，该机制使用优先影响脊髓环境中白血病细胞的细胞。我们建议研究三个具体目的：（1）开发一种基于机制的治疗策略，以利用Cystine半胱氨酸GSH GSH代谢中的基质-CLL细胞间相互作用作为一种独特的途径，以将胱氨酸类似物转化为有毒代谢物，能够选择可选择杀死斑块中的白血病细胞的有毒代谢物。 （2）研究在存在基质细胞的情况下优先针对CLL细胞的胱氨酸类似物的高治疗选择性，并检查基本机制。 （3）使用几种CLL小鼠模型测试新型药物的体内治疗活性，该活性通过劫持基质CLL的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。意义：这项研究将大大推动我们在生物化学水平上对白血病 - 基质相互作用的低估，以及这种细胞间代谢通信在白血病细胞存活和耐药性中的作用。这项研究还将导致新型治疗策略的发展，以有效地杀死体内基质微环境中的CLL。目前，没有有效的疗法来克服由保护性基质微环境引起的CLL耐药性。提出的研究将通过制定一种新的策略来填补这一显着空白，以将保护性基质细胞变成一种代谢机制，该机械可产生活性代谢物，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。