Pharmacogenetics in children with high-risk neuroblastoma

描述(申请人提供)：这项工作的长期目标是通过个性化癌症治疗和/或药物遗传学的环磷酰胺(CY)剂量来提高新诊断的高危神经母细胞瘤儿童的总体存活率。环磷酰胺是大多数儿童癌症患者初始治疗联合化疗方案的重要组成部分。目前的CY按体表面积或体重给药的方法导致CY及其代谢物的全身暴露有相当大的患者间变异性，以血浆浓度-时间曲线(AUC)下的面积表示。CY的细胞毒性代谢物的主要前体4-羟基环磷酰胺(4HCY)暴露的可变性可能是患者间CY疗效差异的原因。我们的工作假设是，参与4HCY产生和消除的酶和转运蛋白的多态性与4HCY/CY AUC的较高比率、提高的诱导反应率有关，从而改善了无事件生存率。我们将检验一种假设，即参与产生和消除4HCY的药物代谢酶和转运体的遗传多态与新诊断的高危神经母细胞瘤儿童对高剂量拓扑替康/环磷酰胺(TopoCY)诱导方案的反应有关。这一目标将作为儿童肿瘤学小组第三阶段试验ANBL0532的相关研究完成，该试验于2012年2月完成。我们收集了380名ANBL0532名参与者的生殖系DNA，所有人都接受了相同的TopoCY诱导化疗方案，为期两个周期，然后再接受四个多药化疗周期。对topoCY的诱导反应是主要终点，3年无事件生存是次要终点。在高危神经母细胞瘤患者中，诱导反应与总存活率相关，因此，最大化诱导反应将提高总存活率。使用候选基因方法，我们在接受环磷酰胺化疗的神经母细胞瘤或其他癌症患者中，鉴定了22个调控酶的基因，涉及4HCY形成的调控酶或参与4HCY消除的调控酶或转运，或与结果相关但与4HCY药代动力学无关的调控蛋白。我们试图评估这些候选基因的多态是否与topoCY诱导反应率和3年无事件生存率有关，长期目标是提高高危神经母细胞瘤儿童的总体生存率。这项建议非常符合NCI计划公告(PAR-12-144)的主要重点，因为这项拨款建议对现有数据进行二次分析，以提出对基于CY的组合治疗和患者预后的改进和评估。

DESCRIPTION (provided by applicant): The long-range goal of this work is to improve overall survival in children with newly-diagnosed high-risk neuroblastoma by personalizing cancer treatment and/or cyclophosphamide (CY) doses by pharmacogenetics. CY is an essential component of initial curative combination chemotherapy regimens for the majority of pediatric cancer patients. The current method of dosing CY by body surface area or weight leads to considerable interpatient variability in the systemic exposure, expressed as area under the plasma concentration-time curve (AUC), of CY and its metabolites. Variability in the exposure to 4- hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of CY, may account for interpatient differences in the efficacy of CY. Our working hypothesis is that polymorphisms of enzymes and transporters involved in the production and elimination of 4HCY are associated with a higher ratio of 4HCY/CY AUC, improved induction response rates, and thus, improved event free survival. We will test the hypothesis that genetic polymorphisms of the drug metabolizing enzymes and transporters involved in the production and elimination of 4HCY are associated with response to a dose-intense topotecan/cyclophosphamide (topoCY) induction regimen in children with newly diagnosed high-risk neuroblastoma. This aim will be completed as a correlative study to a phase III Children's Oncology Group trial, ANBL0532, which completed accrual in February 2012. We have collected germline DNA from 380 ANBL0532 participants, all of whom received the same induction chemotherapy regimen of topoCY for two cycles followed by four additional cycles of multi-agent chemotherapy. Induction response to topoCY is the primary endpoint, and 3-year event-free survival is the secondary endpoint. In patients with high-risk neuroblastoma, induction response is associated with overall survival and thus, maximizing induction response will improve overall survival. Using the candidate gene approach, we identified 22 genes regulating enzymes involved in 4HCY formation, regulating enzymes or transport involved in 4HCY elimination, or regulating proteins associated with outcomes, but not apparently associated with 4HCY pharmacokinetics, in neuroblastoma or other cancer patients receiving CY-based chemotherapy. We seek to evaluate if polymorphisms in these candidate genes are associated with topoCY induction response rates and 3-year event free survival, with the long-range goal of improving overall survival in children with high-risk neuroblastoma. This proposal fits well within the major focus o the NCI Program Announcement (PAR-12-144), as this grant proposes to conduct a secondary analysis of existing data to propose improvements and evaluations of CY- based combinatorial treatments and patients' prognoses.