Epigenetic Regulation in High-Risk Leukemia

高危白血病的表观遗传调控

基本信息

批准号：
9397319
负责人：
Jonathon Payne
金额：
$ 4.74万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9397319
关键词：
Acute Lymphocytic Leukemia Affect Alleles Award B cell differentiation B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Basic Science Binding Bone Marrow Caring Cells Cessation of life Child Childhood Precursor B Lymphoblastic Leukemia Clinical Trials Collaborations Combined Modality Therapy Communication Data Disease Drug Combinations Epigenetic Process Extramural Activities Fellowship Folic Acid Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Goals Harvest Health Hematopoietic Neoplasms Hematopoietic stem cells Human In Vitro Knowledge Laboratories Lead Leadership Learning Malignant - descriptor Malignant Childhood Neoplasm Mediating Mediator of activation protein Mentors Methotrexate Molecular Monitor Mus Mutation Outcome Pathway interactions Patient-Focused Outcomes Patients Pennsylvania Pharmacology Pharmacotherapy Physicians Play Pre-Clinical Model Repression Research Research Activity Research Training Resistance Resources Role Scientist Technical Expertise Testing Therapeutic Therapeutic Effect Training Transplantation Treatment Efficacy Tumor Suppression Tumor Suppressor Proteins Universities Xenograft Model Xenograft procedure casein kinase II cytotoxic differentiated B cell epigenetic regulation experience experimental study folic acid metabolism graduate medical education high risk in vivo inhibitor/antagonist knowledge base leukemia leukemogenesis overexpression preclinical study promoter relapse risk skills targeted treatment tumorigenesis

项目摘要

SUMMARY The overall goal of the proposed training plan is to develop the fellowship applicant's fundamental knowledge, conceptual frameworks, research expertise, and professional skills to maximize his impact as a physician- scientist. This will be accomplished by an educational and research training plan through which the applicant will: 1) develop the knowledge base and technical expertise required to determine the epigenetic mechanisms of gene regulation in health and disease, 2) learn to integrate basic science discoveries with patient data to develop preclinical studies that lead to clinical trials and new standards of care, and 3) develop professional skills in communication, collaboration, and leadership. These goals will be achieved through a unique, inter-campus research training plan that integrates the resources of two universities to provide graduate and medical education (Loma Linda University) with an extramural research training experience (Pennsylvania State University). Research activities will focus on high-risk pediatric B-cell acute lymphoblastic leukemia (B-ALL) and upstream mediators of epigenetic regulation that can be targeted for treatment. Data from the research mentor/sponsor's laboratory implicate Casein Kinase II (CK2) as a major player in this disease and suggest that combination therapies targeting CK2 and its downstream pathways could be a game changer in the treatment of high-risk B-ALL. The overall goal of the research training plan is to define the role of CK2 in the oncogenesis of B-ALL and to evaluate the efficacy and epigenetic mechanisms of combination therapy targeting the CK2 pathway in high-risk B-ALL. CK2 functionally inactivates the Ikaros tumor suppressor. Pharmacological inhibition of CK2 can restore Ikaros' ability to regulate transcription in high- risk B-ALL. We have also demonstrated that treatment with the CK2 inhibitor, CX-4945, has therapeutic efficacy in patient-derived xenograft (PDX) models of high-risk B-ALL. These discoveries establish the feasibility of CK2 inhibitors as a targeted treatment for high-risk B-ALL. They also suggest that CK2 contributes to B-ALL oncogenesis by functionally inactivating the Ikaros tumor suppressor. Our recent preliminary data indicates that CK2 interferes with Ikaros' ability to repress transcription of genes associated with the folic acid metabolism pathway. High expression of these genes in leukemia is associated with resistance to the folic acid pathway inhibitor, methotrexate. Our overall hypothesis is that overexpression of CK2 plays a role in B-ALL oncogenesis through its effects on Ikaros-mediated tumor suppression. We also hypothesize that CK2 inhibitors can be used in combination with therapeutics that act on Ikaros targets (folic acid pathway genes) to effectively treat high-risk B-ALL. To test these hypotheses we propose the following aims: Specific Aim 1: Establish the therapeutic efficacy and epigenetic mechanisms of combination treatment with CK2 inhibitor and folic acid pathway inhibitor (methotrexate) in a preclinical model of high-risk B-cell acute lymphoblastic leukemia. Specific Aim 2: Determine the role of CK2 in leukemogenesis.

概括拟议培训计划的总体目标是培养奖学金申请人的基础知识，概念框架、研究专业知识和专业技能，以最大限度地发挥他作为医生的影响力- 科学家。这将通过教育和研究培训计划来完成，申请人可以通过该计划将：1）开发确定表观遗传所需的知识库和技术专长健康和疾病中的基因调控机制，2）学会整合基础科学发现利用患者数据开展临床前研究，从而进行临床试验和新的护理标准， 3) 培养沟通、协作和领导方面的专业技能。这些目标将是通过独特的校园间研究培训计划实现，该计划整合了两个学院的资源提供研究生和医学教育并进行校外研究的大学（罗马琳达大学）培训经验（宾夕法尼亚州立大学）。研究活动将重点关注高风险儿科 B 细胞急性淋巴细胞白血病（B-ALL）和可针对的表观遗传调控上游介质治疗。来自研究导师/资助者实验室的数据表明酪蛋白激酶 II (CK2) 是一个主要的并建议针对 CK2 及其下游通路的联合疗法可能会改变高风险 B-ALL 治疗的游戏规则。研究训练计划的总体目标是确定 CK2 在 B-ALL 肿瘤发生中的作用并评估其功效和表观遗传机制针对高危 B-ALL 的 CK2 通路联合治疗的研究。 CK2 功能性地灭活 Ikaros 肿瘤抑制剂。 CK2 的药理学抑制可以恢复 Ikaros 在高转录水平中调节转录的能力。风险B-ALL。我们还证明，使用 CK2 抑制剂 CX-4945 进行治疗具有治疗作用。在高危 B-ALL 患者来源的异种移植 (PDX) 模型中的疗效。这些发现确立了 CK2抑制剂作为高危B-ALL靶向治疗的可行性。他们还表明 CK2 有助于通过功能性失活 Ikaros 肿瘤抑制因子来抑制 B-ALL 肿瘤发生。我们最近的初步数据表明 CK2 干扰 Ikaros 抑制叶酸相关基因转录的能力代谢途径。这些基因在白血病中的高表达与对叶酸的抵抗有关途径抑制剂，甲氨蝶呤。我们的总体假设是 CK2 的过度表达在 B-ALL 中发挥作用通过其对 Ikaros 介导的肿瘤抑制的影响来实现肿瘤发生。我们还假设 CK2 抑制剂可与作用于 Ikaros 靶标（叶酸途径基因）的治疗药物联合使用，以有效治疗高危B-ALL。为了检验这些假设，我们提出以下目标：具体目标 1：建立CK2联合治疗的疗效和表观遗传机制抑制剂和叶酸途径抑制剂（甲氨蝶呤）在高危 B 细胞急性临床前模型中的应用淋巴细胞白血病。具体目标 2：确定 CK2 在白血病发生中的作用。