Novel Strategies to Target Leukemia-Stromal Interactions

描述(申请人提供)：我们实验室和其他实验室以前的研究表明，慢性淋巴细胞白血病(CLL)细胞表现出ROS生成增加，这种氧化应激使白血病细胞高度依赖细胞抗氧化系统，如谷胱甘肽(GSH)来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来减轻氧化应激，促进其存活和耐药性，其机制是通过半胱氨酸转化和穿梭于两个细胞间的细胞间代谢通讯来促进GSH的合成。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细胞对基质细胞氧化还原平衡和细胞存活的依赖揭示了CLL细胞的致命弱点，可以作为治疗的靶点。本研究的主要目的是验证一个假设，即骨髓基质细胞和CLL细胞在半胱氨酸/半胱氨酸/GSH代谢过程中的代谢通讯可以作为一种新的机制，利用优先影响基质环境中的白血病细胞的药物选择性地杀伤白血病细胞。我们建议研究三个特定的目标：(1)开发一种新的基于机制的治疗策略，利用半胱氨酸GSH代谢中基质-CLL细胞间的相互作用作为一种独特的途径，将半胱氨酸类似物转化为毒性代谢物，能够选择性地杀死基质微环境中的白血病细胞。(2)研究在有基质细胞存在的情况下，优先靶向CLL细胞的半胱氨酸类似物的高治疗选择性，并检测其潜在的机制。(3)采用几种CLL小鼠模型，通过劫持间质-CLL细胞间代谢途径，在体内有效杀伤间质微环境中的CLL细胞，检测新型药物的体内治疗活性。意义：这项研究将大大促进我们在生化水平上对白血病-间质相互作用的了解，以及这种细胞间代谢通讯在白血病细胞生存和耐药性中的作用。这项研究还将有助于开发新的治疗策略，在体内有效地杀死间质微环境中的CLL。目前还没有有效的治疗方法来克服保护性基质微环境导致的CLL耐药。这项拟议的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变为一种代谢机制，产生活性代谢产物，选择性地杀死组织微环境中的白血病细胞，从而对慢性粒细胞白血病患者的临床治疗具有重要的治疗意义。

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.