Targeting PML for leukemia therapy.

针对 PML 进行白血病治疗。

基本信息

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
项目类别：
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

项目摘要

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）：已证明白血病的维持取决于具有自我更新特性的散装白血病种群中细胞的少量亚群，并被称为“白血病发射细胞”（LICS）。 LIC具有常规干细胞的机械性能，包括更静态的性质，这被认为可以介导其对基于标准化疗的治疗的抗性。无法有效靶向LIC会导致疾病复发。慢性粒细胞性白血病（CML）是一种广泛研究的干细胞疾病，在该干细胞疾病中，LIC池并非总是通过当前的靶向疗法消除，从而导致药物停用后疾病复发。我们已经证明，在常规造血干细胞（HSC）和CML爆炸中，临床细胞性白血病（PML）抑制肿瘤的表达都高得多，并且PML表达的丧失预示了CML中更有利的结果。随后，我们证明了PML在保持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知之甚少。还已知PML在药理上通过用砷处理细胞受到药理抑制，这特别降低了蛋白质的稳定性。利用这一点，我们在CML的小鼠模型中使用了PML的砷介导的烧蚀来成功靶向LIC。但是，需要评估PML靶向的有效性。因此，为了了解LIC维持所需的下游PML的关键途径，并将PML的LIC靶向转换为诊所，我们提出了以下特定目的：（1）研究PML在静态LIC中的分子功能及其在LICS与骨Marrow Niche之间的杂种中的作用；（2）评估在更临床相关的CML小鼠模型中砷处理的有效性；（3）为慢性期CML的砷+dasatinib治疗组合制定临床试验。这些目标的实现可以大大改善CML患者的治疗方法，从而可能允许在消除LIC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标。公共卫生相关性：我们已经定义了PML在维持CML启动细胞中的重要作用，并提出了一种新的治疗方法，用于靶向静止的白血病启动细胞（LIC），通过使用砷抑制PML的功能。我们的发现支持以下观点：砷的PML启动可能是使CML发射细胞对抗肿瘤治疗更敏感的有效工具。这项工作有可能对CML的治疗产生重大影响。酪氨酸激酶抑制剂成功地抑制了大多数CML患者的恶性克隆。然而，该疾病在停用治疗后会浮出水面，一部分患者发展出对TKI治疗具有抗性的疾病。在此提案中，我们将评估将砷与TKI疗法相结合的影响，目的是靶向LIC，以便为这种疾病提供治疗而不是抑制治疗。 PML调节LIC池维持的机制的阐明反过来可能导致治疗白血病的新型治疗方法。