Glucocorticoids in Lymphoblastic Leukemia

 描述(申请人提供)：尽管儿童急性淋巴细胞性白血病(ALL)的治愈率已提高到85%以上，但这些治疗方法都伴随着急性和长期不良反应的高比率。大量使用糖皮质激素(如地塞米松)和天冬酰胺酶有助于提高治愈率和毒副作用。我们的工作表明，天冬酰胺酶深刻地影响地塞米松的药代动力学，这两种药物的相互作用既影响疗效，也影响毒性。在之前的资助期间，我们建立了第一个小鼠骨坏死(On)模型，结果表明，间断地塞米松对骨坏死的作用弱于地塞米松，但抗白血病作用并不比持续地塞米松低，天冬酰胺酶增加了地塞米松诱导的On的频率，On的近端机制是药物引起的供骨易感血管的动脉病变。此外，我们自己的团队和其他人产生的临床数据已经确定了天冬酰胺酶和地塞米松引起的几种不良反应的治疗相关和遗传基因组风险因素，包括ON和胰腺炎，以及所有复发的遗传风险因素。我们已经证明，天冬酰胺酶全身暴露不仅影响地塞米松的药代动力学，而且还影响复发和所有复发的风险，说明天冬酰胺酶和地塞米松对临床结果的相互作用。我们发现ON的遗传风险因素涉及谷氨酸受体基因组变异，血浆蛋白质组学分析证明患有ON的小鼠比没有ON的小鼠有更高的γ-谷氨酰水解酶，而天冬酰胺酶治疗直接增加了血浆中的谷氨酸浓度。然而，谷氨酸途径影响地塞米松/天冬酰胺酶诱导的不良反应风险的机制仍不清楚，同样，也不知道易导致一种不良反应(如ON)的基因组变异是否会影响其他不良反应(如胰腺炎)的风险或预期的抗白血病效果。为了从实验上解决这些问题，我们正在使用我们对ON风险因素的广泛临床研究的结果(通过其他机制资助)，在我们的综合小鼠模型(在过去的资助期间开发)中优先研究宿主和治疗相关的ON风险因素，以评估地塞米松和天冬酰胺酶联合治疗的疗效和抗白血病效果。在目标1中，我们将测试治疗方案对ON频率的影响，并对抗白血病效果和胰腺毒性进行二次分析。在目标2中，我们将测试生化干扰谷氨酸途径(通过补充谷氨酸和受体拮抗)对ON诱导的地塞米松和天冬酰胺酶的影响，并对抗白血病和不良胰腺作用进行二次分析。在目标3中，我们将测试特定生殖系基因组变异对ON频率的影响，并对抗白血病和胰腺效应进行二次分析。我们的长期目标是改进糖皮质激素和天冬酰胺酶的使用，在不影响抗白血病效果的情况下将不良反应降至最低。

 DESCRIPTION (provided by applicant): Although cure rates in childhood acute lymphoblastic leukemia (ALL) have increased to over 85%, these cures are accompanied by a high rate of both acute and long term adverse effects. The intense use of both glucocorticoids (e.g. dexamethasone) and asparaginase contributes to both high cure rates and toxic effects. Our work has shown that asparaginase profoundly affects dexamethasone pharmacokinetics, and that interaction of these two drugs influences both efficacy and toxicity. In the prior funding period, we developed the first murine model of osteonecrosis (ON), showed that discontinuous dexamethasone is less osteonecrotic but not less antileukemic than continuous exposure to dexamethasone, that asparaginase increases the frequency of dexamethasone-induced ON, and that the proximal mechanism of ON is a drug-induced arteriopathy in the vessels supplying susceptible bone. Moreover, clinical data generated by our own group and others have identified treatment-related and inherited genomic risk factors for several adverse effects caused by asparaginase and dexamethasone, including ON and pancreatitis, as well as genetic risk factors for ALL relapse. We have shown that asparaginase systemic exposure affects not only dexamethasone pharmacokinetics but also the risk of ON and of ALL relapse, illustrating the interplay between asparaginase and dexamethasone on clinical outcomes. We found that genetic risk factors for ON involve glutamate receptor genomic variants, that proteomic analysis of plasma documented higher gamma glutamyl hydrolase in mice with vs without ON, and asparaginase treatment directly increases plasma concentrations of glutamate. However, the mechanisms whereby the glutamate pathway affects the risk of dexamethasone/asparaginase- induced adverse effects remain unclear, and likewise it is not known whether genomic variation that predisposes to one adverse effect (e.g. ON) may impact the risk of other adverse effects (e.g. pancreatitis) or the desired antileukemic effects. To address these questions experimentally, we are using findings from our extensive clinical studies of ON risk factors (funded via other mechanisms) to prioritize the study of host- and treatment-related risk factors for ON in our integrated murine models (developed during the past funding period) for assessing ON and antileukemic effects after dexamethasone combined with asparaginase. In Aim 1, we will test the impact of treatment schedule on the frequency of ON, with secondary analyses of antileukemic effect and pancreatic toxicity. In Aim 2, we will test the impact of biochemically perturbing the glutamate pathway (via glutamate supplementation and receptor antagonism) on dexamethasone- and asparaginase induced ON, with secondary analyses of antileukemic and adverse pancreatic effects. In Aim 3, we will test the impact of specific germline genomic variation on the frequency of ON, with secondary analysis of antileukemic and pancreatic effects. Our long term goal is to improve the use of glucocorticoids and asparaginase to minimize adverse effects without compromising antileukemic effectiveness.