Glucocorticoids in Lymphoblastic Leukemia

糖皮质激素治疗淋巴细胞白血病

基本信息

批准号：
8396685
负责人：
MARY V RELLING
金额：
$ 9.96万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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/8396685
关键词：
10 year old 6-Mercaptopurine Abbreviations Acute Acute Lymphocytic Leukemia Address Adipocytes Adolescent Adrenal Glands Adult Adverse effects Adverse event Affect Age Am 80 Area Arthritis Asthma Autoimmune Diseases Avascular necrosis of bone Blood Cell Count Blood Vessels Bone necrosis CYP3A4 gene Cancer Therapy Evaluation Program Cessation of life Child Childhood Acute Lymphocytic Leukemia Children&apos s Oncology Group Classification Clinical Clinical Data Clinical Trials Cortisone Coupled Dexamethasone Dose Dose-Limiting Effectiveness Embolism Equilibrium Event Extensive Necrosis Fatty acid glycerol esters Frequencies Future Gender Genes Genetic Polymorphism Glucocorticoids Goals Green Fluorescent Proteins Head Human Hunger Hydrocortisone Hyperglycemia Hypertrophy Incidence Inhibitory Concentration 50 Joints Kidney Diseases Knowledge Laboratory Study Lead Letters Leukemic Cell Lymphoblastic Leukemia MTHFR gene Malignant Childhood Neoplasm Medicine Methotrexate Methylenetetrahydrofolate reductase (NADPH)Modeling Mus Mutation National Cancer Institute Necrosis Non obese Operative Surgical Procedures Oral Organ Transplantation Osteopenia Patients Pharmacodynamics Phenotype Philadelphia Chromosome Plasma Plasminogen Activator Inhibitor 1 Pre-Clinical Model Predisposition Prednisone Quality of life Randomized Regimen Relapse Replacement Arthroplasty Risk Risk Factors Schedule Series Serious Adverse Event Serum Solid Steroids Thymidylate Synthase Time Toxic effect Translational Research Trees Vascular blood supply Vasculitis Wild Type Mouse Withdrawal Work abl Oncogene adverse outcome antileukemic agent asparaginase attenuation bone cancer therapy design diabetic high risk improved leukemia mouse model pressure public health relevance success

项目摘要

DESCRIPTION (provided by applicant): Cure rates in childhood acute lymphoblastic leukemia (ALL) have increased to over 80%. Current therapies depend heavily upon the intense use of glucocorticoids, particularly dexamethasone, in addition to multiple other antileukemic agents. The major dose-limiting adverse effect of glucocorticoids in modern ALL clinical trials is glucocorticoid-induced osteonecrosis or avascular necrosis. Glucocorticoid-induced osteonecrosis has long been known to be related to glucocorticoid exposure in adults and children treated for solid organ transplant, nephropathies, asthma, arthritis, and other autoimmune diseases. Our group and others have identified putative treatment-related and host-related risk factors influencing glucocorticoid-induced osteonecrosis. However, any changes to therapy to attempt to decrease the risk of this adverse effect must be weighed against the possible attenuation of desired antileukemic effects. Thus, preclinical models that allow for the characterization of treatment-related and host-related risk factors for osteonecrosis are needed, but they must be coupled with studies on how those same factors affect effectiveness (i.e., relapse risk). Our group has spent the last two years developing the first murine model for glucocorticoid-induced osteonecrosis, as the necessary platform for extending our prior studies of risk factors in children with ALL. Using our clinical data as the impetus for our laboratory studies in murine models, our goal is to fully elucidate treatment-related and host-related risk factors for glucocorticoid-induced osteonecrosis, and to evaluate the influence of these risk factors on antileukemic effectiveness. These translational research questions cannot be addressed in patients. Three aims are proposed: to compare the frequency of osteonecrosis following discontinuous vs continuous dexamethasone in a multiagent regimen; to compare the antileukemic effects of discontinuous vs continuous dexamethasone in two murine models of ALL; and to compare the osteonecrotic vs antileukemic effects of dexamethasone in mice that are wild-type, hemizygous, and homozygous deficient for germline genetic defects identified as related to clinical susceptibility to osteonecrosis. Our long term objective is to design less toxic glucocorticoid-containing regimens for ALL that do not compromise desired antileukemic effectiveness. PUBLIC HEALTH RELEVANCE: Glucocorticoids (steroids such as cortisone, prednisone, dexamethasone) are among the most commonly prescribed medicines in use today. These medicines are very effective against the most common childhood cancer, a type of leukemia. However, they have a serious side effect: avascular necrosis of bone or osteonecrosis. In this proposal, we will use our knowledge of leukemia therapy and state-of-the-art mouse models to work out schedules of medicines that maintain cure rates for leukemia but are less toxic to bone than current schedules.

描述（由申请人提供）：儿童急性淋巴细胞白血病（ALL）的治愈率已提高至 80% 以上。目前的治疗在很大程度上依赖于糖皮质激素的大量使用，尤其是地塞米松，以及多种其他抗白血病药物。现代 ALL 临床试验中糖皮质激素的主要剂量限制性不良反应是糖皮质激素引起的骨坏死或缺血性坏死。长期以来，人们已知糖皮质激素引起的骨坏死与接受实体器官移植、肾病、哮喘、关节炎和其他自身免疫性疾病治疗的成人和儿童的糖皮质激素暴露有关。我们的小组和其他人已经确定了影响糖皮质激素引起的骨坏死的假定的治疗相关和宿主相关的危险因素。然而，任何试图降低这种不良反应风险的治疗改变都必须权衡所需的抗白血病作用可能减弱的情况。因此，需要能够表征骨坏死的治疗相关和宿主相关危险因素的临床前模型，但它们必须与这些相同因素如何影响有效性（即复发风险）的研究相结合。我们的团队在过去两年里开发了第一个糖皮质激素引起的骨坏死的小鼠模型，作为扩展我们之前对 ALL 儿童危险因素研究的必要平台。利用我们的临床数据作为小鼠模型实验室研究的动力，我们的目标是充分阐明糖皮质激素引起的骨坏死的治疗相关和宿主相关危险因素，并评估这些危险因素对抗白血病有效性的影响。这些转化研究问题无法在患者身上得到解决。提出了三个目标：比较多药治疗方案中不连续与连续地塞米松后发生骨坏死的频率；比较间断与连续地塞米松在两种 ALL 小鼠模型中的抗白血病作用；并比较地塞米松对野生型、半合子和纯合子小鼠的骨坏死与抗白血病作用，这些小鼠被确定与骨坏死的临床易感性相关的种系遗传缺陷有缺陷。我们的长期目标是为 ALL 设计毒性较低的含糖皮质激素的治疗方案，且不损害所需的抗白血病效果。公共卫生相关性：糖皮质激素（类固醇，如可的松、泼尼松、地塞米松）是当今最常用的处方药物之一。这些药物对最常见的儿童癌症（一种白血病）非常有效。然而，它们有严重的副作用：骨缺血性坏死或骨坏死。在这项提案中，我们将利用我们在白血病治疗方面的知识和最先进的小鼠模型来制定药物时间表，以维持白血病的治愈率，但对骨骼的毒性比目前的时间表要小。