Pharmacogenetics in children with high-risk neuroblastoma

描述（由申请人提供）：这项工作的长期目标是通过药物遗传学个性化癌症治疗和/或环磷酰胺（CY）剂量来提高新诊断的高危神经母细胞瘤儿童的总生存率。CY是大多数儿童癌症患者初始治愈性联合化疗方案的重要组成部分。目前按体表面积或体重给予CY的方法导致CY及其代谢产物的全身暴露量（以血浆浓度-时间曲线下面积（AUC）表示）存在相当大的患者间差异。暴露于4-羟基环磷酰胺（4 HCY）（CY细胞毒性代谢物的主要前体）的变异性可能是CY疗效的患者间差异的原因。我们的工作假设是，参与4 HCY产生和消除的酶和转运蛋白的多态性与较高的4 HCY/CY AUC比率、改善的诱导应答率以及因此改善的无事件生存率相关。我们将检验一个假设，即参与4 HCY产生和消除的药物代谢酶和转运蛋白的遗传多态性与新诊断的高危神经母细胞瘤儿童对剂量密集的拓扑替康/环磷酰胺（topoCY）诱导方案的反应相关。这一目标将作为III期儿童肿瘤组试验ANBL 0532的相关研究完成，该试验于2012年2月完成招募。我们从380名ANBL 0532参与者中收集了生殖系DNA，所有参与者都接受了两个周期的topoCY诱导化疗方案，然后再进行四个周期的多药化疗。对topoCY的诱导应答是主要终点，3年无事件生存期是次要终点。在高危神经母细胞瘤患者中，诱导应答与总生存期相关，因此，最大化诱导应答将改善总生存期。使用候选基因的方法，我们确定了22个基因调节酶参与4 HCY形成，调节酶或运输参与4 HCY消除，或调节蛋白质与结果，但没有明显相关的4 HCY药代动力学，在神经母细胞瘤或其他癌症患者接受CY为基础的化疗。我们试图评估这些候选基因的多态性是否与topoCY诱导反应率和3年无事件生存率相关，长期目标是提高高危神经母细胞瘤儿童的总生存率。该提案非常符合NCI计划公告（PAR-12-144）的主要重点，因为该资助计划对现有数据进行二次分析，以提出基于CY的组合治疗和患者疾病的改进和评估。

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.