Targeting PML for leukemia therapy.

针对 PML 进行白血病治疗。

• 批准号: 7768030
• 负责人: PIER PAOLO PANDOLFI
• 金额: $ 47.33万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768030
• 关键词: Ablation; Acute Promyelocytic Leukemia; Address; Arsenic; Arsenic Trioxide; Blast Cell; Bone Marrow; Bone Marrow Cells; Cell Cycle Regulation; Cell Maintenance; Cells; Cellular biology; Characteristics; Chronic Myeloid Leukemia; Chronic-Phase Myeloid Leukemia; Clinic; Clinical Trials; Combined Modality Therapy; Cytogenetics; Dasatinib; Data; Defect; Development; Disease; Disease Progression; Disease Reservoirs; Disease remission; Effectiveness; Failure; Genes; Genetic; Goals; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Imatinib; Imatinib mesylate; Injury; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Cytogenetics; Nature; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Property; Proteins; Recurrence; Recurrent disease; Resistance; Role; Safety; Sirolimus; Solid; Stem cells; Therapeutic; Toxic effect; Translating; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Work; base; bcr-abl Fusion Proteins; cancer stem cell; cell growth; chemotherapy; clinically relevant; efficacy testing; experience; high risk; human FRAP1 protein; improved; inhibitor/antagonist; leukemia; leukemic stem cell; mTOR inhibition; mouse model; multicatalytic endopeptidase complex; novel therapeutic intervention; phase 1 study; preclinical study; prevent; public health relevance; response; self-renewal; therapeutic target; tool; tumor; tyrosine kinase ABL1

DESCRIPTION (provided by applicant): Maintenance of leukemia has been demonstrated to be dependent upon a small sub-population of cells within the bulk leukemic population that have self-renewal properties and are termed "leukemia-initiating cells" (LICs). LICs share mechanistic properties with regular stem cells including a more quiescent nature, which is thought to mediate their resistance to standard chemotherapy-based treatment. Failure to effectively target LICs can result in disease relapse. Chronic Myelogenous Leukemia (CML) is an extensively studied stem cell disorder in which the LIC pool is not always eradicated by current targeted therapy, leading to disease relapse upon drug discontinuation. We have demonstrated that expression of the Promyelocytic Leukemia (PML) tumor suppressor is surprisingly high in both regular hematopoietic stem cells (HSCs) and in CML blasts and that loss of PML expression predicts a more favorable outcome in CML. We subsequently demonstrated that PML plays a key role in maintaining the quiescence and self-renewal properties of HSCs/LICs although the exact molecular mechanisms involved are poorly understood. PML is also known to be pharmacologically inhibited by treatment of cells with arsenic, which specifically decreases the stability of the protein. Taking advantage of this, we have used arsenic-mediated ablation of Pml in a mouse model of CML to successfully target LICs. However, the effectiveness of PML targeting in the clinic needs to be assessed. Therefore, in order to understand the key pathways downstream PML required for LIC maintenance and to translate PML-ablative LIC targeting to the clinic we propose the following Specific Aims: (1) to study the molecular function of PML in quiescent LICs and its role in the cross-talk between LICs and the bone marrow niche; (2) to assess effectiveness of arsenic treatment in more clinically relevant mouse models of CML; (3) to develop a clinical trial of combination arsenic+dasatinib treatment for chronic phase CML. Accomplishment of these aims could greatly improve treatment of patients with CML, possibly allowing discontinuation of therapy after LIC eradication. Further, understanding PML function could provide other therapeutic targets for LIC and cancer stem cell ablation. PUBLIC HEALTH RELEVANCE: We have defined the essential role of PML in the maintenance of CML-initiating-cells, and present a new therapeutic approach for targeting quiescent leukemia initiating cells (LICs) by using arsenic to inhibit the function of PML. Our findings support the notion that PML-ablation by arsenic may be an effective tool to render CML-initiating cells more sensitive to anti-tumor therapy. This work has the potential to have a significant impact on the treatment of CML. Tyrosine kinase inhibitors are successful at suppressing the malignant clone in the majority of CML patients. However, the disease recurs upon discontinuation of therapy, and a subset of patients develops disease that is resistant to TKI therapy. In this proposal, we will evaluate the effect of combining arsenic with TKI therapy, with goal of targeting the LICs in order to result in curative rather than suppressive therapy for this disease. The elucidation of the mechanisms by which PML regulates the maintenance of the LIC pool could in turn lead to novel therapeutic approaches to treat leukemia.

描述（由申请人提供）：白血病的维持已被证明依赖于大量白血病群体中具有自我更新特性的一小部分细胞亚群，这些细胞被称为“白血病起始细胞”（lic）。lic与常规干细胞具有相同的机制特性，包括更静息的特性，这被认为介导了它们对基于标准化疗的治疗的抗性。未能有效靶向llic可导致疾病复发。慢性髓性白血病（CML）是一种被广泛研究的干细胞疾病，目前的靶向治疗并不总能根除LIC池，导致停药后疾病复发。我们已经证明早幼粒细胞白血病（PML）肿瘤抑制因子在常规造血干细胞（hsc）和CML原细胞中的表达都惊人地高，PML表达的缺失预示着CML更有利的结果。我们随后证明PML在维持hsc / lic的静止和自我更新特性中起关键作用，尽管所涉及的确切分子机制尚不清楚。在药理学上，PML也被砷处理的细胞所抑制，砷会降低蛋白质的稳定性。利用这一点，我们在CML小鼠模型中使用砷介导的Pml消融来成功靶向LICs。然而，PML靶向治疗在临床中的有效性有待评估。因此，为了了解LIC维持所需的PML下游关键通路，并将PML消融LIC靶向应用于临床，我们提出以下具体目标：(1)研究PML在静止LIC中的分子功能及其在LIC与骨髓生态位之间的串导中的作用；(2)评估砷在临床相关的CML小鼠模型中的治疗效果；(3)开展砷+达沙替尼联合治疗慢性粒细胞白血病的临床试验。这些目标的实现可以极大地改善CML患者的治疗，可能允许在LIC根除后停止治疗。此外，了解PML功能可以为LIC和癌症干细胞消融提供其他治疗靶点。