Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance

靶向白血病生物学和化疗耐药中未折叠的蛋白质反应

• 批准号: 9927608
• 负责人: Stephen Matthew Sykes
• 金额: $ 42.78万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-07 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927608
• 关键词: Acute Myelocytic Leukemia; Address; Affect; American; Ara-C; Automobile Driving; Autophagocytosis; Binding; Biology; Cell Death; Cell Differentiation process; Cell Survival; Cell physiology; Cellular Stress; Chemicals; Cholesterol; Cholesterol Homeostasis; Complex; Cytarabine; DNA Damage; Data; Dependence; Development; Disease; Disease Progression; Doxorubicin; Effectiveness; Experimental Models; Functional disorder; Gene Expression; Gene Order; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Human Cell Line; In Vitro; Karyotype; Length; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Newly Diagnosed; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenocopy; Positioning Attribute; Process; Proteins; Public Health; Recurrent disease; Regulatory Element; Resistance; Role; Safety; Sampling; Signal Transduction; Sterols; Survival Rate; Therapeutic; Toxic effect; Transcript; Treatment Efficacy; Xenograft Model; Xenograft procedure; activating transcription factor; acute myeloid leukemia cell; attenuation; cancer diagnosis; cell behavior; chemotherapy; effective therapy; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; knock-down; leukemia; mutant; novel; novel therapeutic intervention; novel therapeutics; response; small hairpin RNA; small molecule; small molecule inhibitor; standard of care; therapeutic target; therapy resistant; transcription factor; tumor; uptake; young adult

Project Summary/Abstract Acute myeloid leukemia (AML) is an aggressive blood cancer that encompasses a variety of genetically distinct sub-types. AML patients overall, display one of the lowest overall 5-year survival rates (<25%) of all cancer diagnoses and currently ranks as the deadliest form of leukemia. These unsatisfactory outcomes are largely the result of the ineffectiveness and toxicities of existing chemotherapies and highlight the urgent need for more-effective therapies that either replace or improve the effectiveness these chemotherapies. The development of more-effective therapies begins by identifying the molecular mechanisms that underpin AML pathogenesis and chemotherapy ineffectiveness. We recently discovered that the two transcription factors (TFs) TFs, ATF4 and XBP1s, which are components of the signal transduction network, the unfolded protein response (UPR), are key mediators of AML cell survival and disease progression. Specifically, we have found that inhibition of ATF4 or XBP1s antagonizes AML cell survival and disease progression in multiple in vitro and in vivo models of AML. We also found that small-molecule inhibitors of PERK and IRE1, which are upstream activators of ATF4 and XBP1s, respectively, antagonizes AML cell survival and enhances the effectiveness of first-line chemotherapies. The collective goals of this proposal aim to address two key unanswered questions: 1. What are the downstream transcriptional targets of ATF4 and XBP1s that support AML biology and 2. What are the molecular nodes of the UPR that can be targeted with chemical strategies? With respect to the first question, we have identified two candidates, DDIT4 and SREBF1, which are known regulators of autophagy and cholesterol biology, respectively. We will use a combination of established genetically engineered mouse models of AML and patient-derived AML samples to assess the functional roles of DDIT4 and SREBF1 in AML as well as their relationship to the UPR. Additionally, we will assess the contribution of DDIT4 and SREBF1 – as well as the downstream-regulated processes contribute to the pro-leukemia functions of ATF4 and XBP1s. Second, we will assess therapeutic strategies for targeting the UPR, autophagy and cholesterol biology either alone or simultaneously in experimental models of AML. The results of these studies will provide new insight on the molecular mechanisms that support the pathogenesis and chemotherapy responses of AML and establish a platform for developing novel therapeutic strategies. Moreover, components of the UPR support the pathophysiology of many other tumor settings and thus results from our proposed studies will likely have implications for other forms of human cancers.

项目摘要/摘要 急性髓样白血病（AML）是一种侵略性的血液癌，包括多种一般 不同的子类型。 AML患者总体显示了所有最低的5年生存率（<25％）之一 癌症诊断，目前是白血病最致命的形式。这些不令人满意的结果是 在很大程度上是现有化学疗法的无效性和毒性的结果，并强调了迫切需求 对于取代或提高这些化学疗法有效性的更有效的疗法。 更有效的疗法的发展首先是确定分子机制 基础AML发病机理和化学疗法无效。我们最近发现这两个 转录因子（TFS）TFS，ATF4和XBP1，它们是信号转导网络的组成部分， 展开的蛋白质反应（UPR）是AML细胞存活和疾病进展的关键介体。 具体而言，我们发现抑制ATF4或XBP1会拮抗AML细胞的存活和疾病 AML的多个体外和体内模型的进展。我们还发现 PERK和IRE1分别是ATF4和XBP1的上游激活剂，分别拮抗AML细胞 生存并提高一线化学疗法的有效性。 该提案的集体目标旨在解决两个关键的未解决问题：1。 支持AML生物学的ATF4和XBP1的下游转录靶标和2。 可以用化学策略靶向的UPR的分子节点？关于第一个问题， 我们已经确定了两个候选人DDIT4和SREBF1，它们是自噬和 胆固醇生物学分别。我们将结合建立的基因工程鼠标 AML和患者衍生的AML样品的模型，以评估DDIT4和SREBF1在AML中的功能作用 以及他们与UPR的关系。此外，我们将评估DDIT4和SREBF1的贡献 - 以及下游调节的过程有助于ATF4和XBP1的促血清血症。 第二，我们将评估针对UPR，自噬和胆固醇生物学的治疗策略 单独或仅在AML的实验模型中。这些研究的结果将提供新的 了解支持AML和AML的发病机理和化学疗法反应的分子机制 建立一个制定新型治疗策略的平台。此外，UPR的组件支持 许多其他肿瘤环境的病理生理学，因此我们提出的研究可能会导致 对其他形式的人类癌症的影响。