Targeting PML for therapy in leukemia-initiating cells

针对 PML 治疗白血病起始细胞

• 批准号: 8548904
• 负责人: Keisuke Ito
• 金额: $ 23.41万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548904
• 关键词: Ablation; Acute; Acute Promyelocytic Leukemia; Address; Arsenic; Arsenic Trioxide; Award; Blast Cell; Bone Marrow; Cell Cycle Regulation; Cell Maintenance; Cell Proliferation; Cells; Chronic Myeloid Leukemia; Clinic; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Dasatinib; Data; Defect; Development; Disease; Disease Reservoirs; Doctor of Philosophy; Effectiveness; Environment; Evaluation; Failure; Genes; Genetic; Goals; Hematologic Neoplasms; Hematologist; Hematopoietic stem cells; Imatinib; Imatinib mesylate; In Vitro; Israel; K-Series Research Career Programs; Knockout Mice; Knowledge; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical center; Mentors; Modeling; Molecular; Mus; Nature; Osteocalcin; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Population; Pre-Clinical Model; Program Development; Property; Proteins; Recurrent disease; Research; Research Personnel; Research Project Grants; Residual Tumors; Resistance; Resources; Role; Safety; Scientist; Sirolimus; Solid; Solid Neoplasm; Stem cells; Therapeutic; Training; Training Programs; Transgenic Mice; Translating; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; University Hospitals; Work; anticancer research; base; cancer stem cell; career; cell growth; chemotherapy; clinically relevant; efficacy testing; experience; human FRAP1 protein; improved; in vivo; leukemia; leukemic stem cell; mTOR inhibition; mouse model; multicatalytic endopeptidase complex; novel therapeutic intervention; pre-clinical; preclinical study; prevent; programs; self-renewal; skills; stem cell biology; success; therapeutic target; tool; tumor

6- PROJECT SUMMARY This proposal describes a five-year training program for the development of an academic career in Cancer Stem Cell Biology. I have four-years of experience as a cancer biologist, two-years as a stem cell biologist, and five-years as a hematologist in a university hospital. I am now planning to expand my knowledge, skills and research field to cancer-initiating cells by combining stem cell and cancer research. My goal over the next five years is to become an independent scientist in the field of cancer stem cell biology, especially in leukemia-initiating cells. I am planning to reach my goal by a two-phase plan. The first phase (first 2-3 years) will be characterized by intense bench work to construct the basis of my research projects and to acquire experience in fields that are new to me, such as the characterization of hematological malignancies in clinically relevant mouse models and contribution of clinical trials in the U.S.A. Further, I will develop/establish niche-specific Pml-deleted mouse models for my own research during independent phase. In the first part of the program, I will be mentored by Pier Paolo Pandolfi, PhD, a leading cancer biologist who has great experience in modeling leukemia and solid tumors in vivo and who has trained numerous independent investigators. The program will be enriched by the collaboration of Drs. D.G. Tenen, D.E. Avigan, T. Suda and J. Teruya-Feldstein. The first part of the award will be completed at Beth Israel Deaconess Medical Center, a scientific environment of excellence with the solid clinical resources necessary to promote the success of this Career Development Award. The second phase will be entirely devoted to establishing my career as an independent scientist. One of the main topics in this phase would be detailed functional analysis of Pml in the microenvironment in niche-specific conditional knockout mice. Five years of support are necessary to produce sufficient data, especially in consideration of the mouse models that I am planning to establish, to allow me to pursue an independent career track. Research will focus on the study of the mechanisms regulating quiescence in leukemia-initiating cells (LICs). Specifically, I am aiming at the development of LIC-specific therapy in paradigmatic hematopoietic stem cell (HSC) disease: chronic myeloid leukemia (CML). 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. I have defined the essential role of PML in the maintenance of CML-initiating-cell, and present a new therapeutic approach for targeting quiescent LICs by pharmacological inhibition of PML. I 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. I 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, I have used arsenic-mediated ablation of Pml in a mouse model of CML to successfully target LICs. This work has the potential to have a significant impact on treatment and eradication of CML. Importantly, my findings support the notion PML-ablation by arsenic might be an effective tool to render CML-initiating cells more sensitive to anti-tumor therapy. However, the effectiveness of PML targeting both in clinically relevant mouse model and 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, I propose the following Specific Aims: (1) to further define the mechanisms of PML-dependent cell cycle regulation in LICs; (2) to analyze the effect of PML loss in the interaction between LICs and their niche; (3) to test the efficacy of arsenic-mediated therapy in preclinical models and finally to support a clinical trial of combination arsenic + Dasatinib treatment for CML through in vitro evaluation. The Training Program outlined in this proposal will launch my independent research career. Importantly, accomplishing 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.

6-项目摘要 该提案描述了一项为期五年的培训计划，以发展癌症的学术生涯 细胞生物学。我有四年的癌症生物学家经验，两年是干细胞生物学家， 在大学医院担任血液学家的五年。我现在正计划扩大我的知识，技能和 通过结合干细胞和癌症研究来研究癌症引发细胞的领域。 在接下来的五年中，我的目标是成为癌症干细胞生物学领域的独立科学家， 特别是在白血病发射细胞中。我计划通过一个两阶段的计划来实现我的目标。第一阶段（第一阶段 2 - 3年）将以强大的基准工作为特征，以构建我的研究项目的基础 获得对我新的领域的经验，例如血液学恶性肿瘤的特征 在美国，临床相关的小鼠模型和临床试验的贡献。此外，我将开发/建立 在独立阶段，用于我自己的研究的利基特异性PML删除的小鼠模型。在第一部分 节目，我将受到领先的癌症生物学家Pier Paolo Pandolfi博士的指导 在体内对白血病和实体瘤进行建模，并培训了众多独立研究者。这 DRS的合作将丰富计划。 D.G. D.E. Tenen Avigan，T。Suda和J. Teruya-Feldstein。 该奖项的第一部分将在贝丝以色列执事医疗中心完成，这是一个科学环境 卓越，以促进该职业发展奖的成功所必需的可靠临床资源。 第二阶段将完全致力于建立我作为独立科学家的职业。主要之一 此阶段的主题将是对小众特异性微环境中PML的详细函数分析 有条件的淘汰小鼠。为了产生足够的数据，必须提供五年的支持，尤其是在 考虑我计划建立的鼠标模型，以使我从事独立职业 追踪。 研究将重点研究调节白血病发射细胞（LIC）中静止的机制。 具体而言，我的目的是开发范式造血干细胞中LIC特异性疗法 （HSC）疾病：慢性髓样白血病（CML）。 已证明白血病的维持取决于细胞内细胞的少量亚群 具有自我更新特性且称为“白血病发射细胞”（LICS）的批量白血病种群。 LIC与常规干细胞共享机械特性，包括更静态的性质，被认为是 介导其对基于标准化疗的治疗的抵抗力。无法有效地瞄准lics会导致 在疾病复发中。慢性骨髓性白血病（CML）是一种广泛研究的干细胞疾病，其中 LIC池并不总是通过当前的靶向疗法消除，导致药物复发 中断。 我已经定义了PML在维持CML发射细胞中的重要作用，并提出了一种新的治疗方法 通过药理学抑制PML靶向静态循环的方法。我已经证明了 临时细胞性白血病（PML）抑制剂的表达在两个常规的情况下都非常高 造血干细胞（HSC）和CML爆炸中，PML表达的丢失预测了更有利的 CML的结果。随后，我证明了PML在保持静止和 HSC/LIC的自我更新特性尽管涉及的确切分子机制知之甚少。 也已知PML在药理学上通过用砷的细胞进行药理抑制，特别是 降低蛋白质的稳定性。利用这一点，我在A中使用了PML的砷介导的消融 CML的小鼠模型成功靶向lics。 这项工作有可能对CML的治疗和消除产生重大影响。重要的是，我的 研究结果支持砷的概念pml-pml-live可能是使CML发射细胞更多的有效工具 对抗肿瘤疗法敏感。但是，PML靶向临床相关小鼠的有效性 需要评估模型和诊所。因此，为了了解下游的关键途径 LIC维护所需的PML并将PML的LIC靶向转换为诊所，我建议 以下特定目的：（1）进一步定义了LIC中PML依赖性细胞周期调节的机制； （2） 分析PML损失在LIC与其利基市场之间相互作用中的影响； （3）测试 临床前模型中的砷介导的疗法，最后支持砷组合的临床试验 达沙替尼通过体外评估治疗CML。 该提案中概述的培训计划将启动我的独立研究生涯。 重要的是，实现这些目标可以大大改善CML患者的治疗，可能允许 减轻批准后的治疗中停用。此外，了解PML功能可以提供其他 LIC和癌症干细胞消融的治疗靶标。