Glucocorticoids in Lymphoblastic Leukemia

描述（由申请人提供）：儿童急性淋巴细胞白血病（ALL）的治愈率已提高到80%以上。目前的治疗严重依赖于糖皮质激素，特别是地塞米松的强烈使用，除了多种其他抗白血病药物。在现代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诱导的骨坏死或缺血性坏死。 长期以来，人们一直认为糖皮质激素诱导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。我们的研究小组和其他人已经确定了影响糖皮质激素诱导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变化都必须与预期抗白血病作用的可能减弱进行权衡。因此，需要允许表征骨坏死的治疗相关和宿主相关风险因素的临床前模型，但它们必须与关于这些相同因素如何影响有效性的研究相结合（即，复发风险）。我们的小组在过去的两年里开发了第一个糖皮质激素诱导的骨坏死的小鼠模型，作为扩展我们先前对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我们在小鼠模型中进行实验室研究的动力，我们的目标是充分阐明糖皮质激素诱导的骨坏死的治疗相关和宿主相关风险因素，并评估这些风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中解决。 提出了三个目标：比较多药方案中间断与连续地塞米松给药后的骨坏死频率;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;比较地塞米松在野生型、半合子和纯合子小鼠中的骨坏死与抗白血病作用，这些小鼠的生殖系遗传缺陷被鉴定为与骨坏死临床易感性相关。我们的长期目标是设计毒性较小的含糖皮质激素的ALL治疗方案，同时不影响预期的抗白血病疗效。 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）是目前最常用的处方药。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，我们将利用我们对白血病治疗的了解和最先进的小鼠模型来制定药物治疗计划，以保持白血病的治愈率，但对骨骼的毒性低于目前的计划。

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.