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：
8006397
负责人：
MARY V RELLING
金额：
$ 38.15万
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/8006397
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）：儿童期急性淋巴细胞白血病（ALL）的治疗率已增加到80％以上。当前的疗法在很大程度上取决于糖皮质激素（尤其是地塞米松）的强烈使用，除了多种其他抗白血病药物外。糖皮质激素在现代所有临床试验中的主要剂量限制不良影响是糖皮质激素诱导的截骨或血管坏死。长期以来，糖皮质激素诱导的截骨症与成人和接受固体器官移植，肾病，哮喘，关节炎和其他自身免疫性疾病的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针对糖皮质激素诱导的截骨性的推定治疗相关和与宿主有关的危险因素。但是，必须权衡试图降低这种不良影响风险的治疗的任何变化，以与可能衰减所需的抗白血病作用的衰减。因此，需要对治疗相关和与宿主相关的骨质症的特征的临床前模型，但必须与有关这些因素如何影响有效性的研究（即复发风险）的研究。在过去的两年中，我们的小组开发了第一个用于糖皮质激素诱导的骨坏死的鼠模型，它是扩展我们先前对所有人危险因素研究的必要平台。使用我们的临床数据作为鼠模型中实验室研究的动力，我们的目标是完全阐明与治疗相关的和宿主相关的危险因素对糖皮质激素诱导的骨坏死，并评估这些危险因素对抗病学效果的影响。这些转化研究问题无法解决患者。提出了三个目的：比较在多种方案中不连续的与连续地塞米松后的截骨症的频率；比较在两个鼠模型中不连续的与连续地塞米松的抗白血病作用；并比较地塞米松在野生型，半合子和纯合的小鼠中的抗血清病作用，因为与临床易感性相关的生殖线遗传缺陷不足。我们的长期目标是设计含有毒性糖皮质激素的较小毒素方案，以使所有不损害所需的抗白血病的效果。公共卫生相关性：糖皮质激素（类固醇，例如可的松，泼尼松，地塞米松）是当今使用的最常见的药物。这些药物对最常见的儿童癌（一种白血病）非常有效。但是，它们具有严重的副作用：骨骼或骨坏死的尸体坏死。在此提案中，我们将利用白血病疗法和最先进的小鼠模型的知识来制定维持白血病治疗率的药物时间表，但对骨骼的毒性比目前的时间表少。