Pharmacogenetics in children with high-risk neuroblastoma

高危神经母细胞瘤儿童的药物遗传学

基本信息

批准号：
8566260
负责人：
Jeannine S McCune
金额：
$ 9.85万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8566260
关键词：
Accounting Adult Age Antineoplastic Agents Area Area Under Curve Body Surface Area Cancer Patient Candidate Disease Gene Cessation of life Chemotherapy-Oncologic Procedure Child Children&apos s Oncology Group Clinical Collaborations Correlative Study Cyclophosphamide Cytochrome P450 DNA Data Disease Disease-Free Survival Dose Drug Kinetics Employee Strikes Enzymes Evaluation Exposure to GSTM1 gene Gene Frequency Genes Genetic Genetic Polymorphism Genotype Glutathione S-Transferase Goals Grant Heterogeneity Isoenzymes Malignant Childhood Neoplasm Malignant Neoplasms Methods Modality NIH Program Announcements Neuroblastoma Newly Diagnosed Outcome Participant Patients Peroxidases Pharmaceutical Preparations Pharmacogenetics Phase Phenotype Phosphoramide Mustard Phosphoramide Mustards Plasma Population Positioning Attribute Process Production Proteins Recording of previous events Refractory Regimen Reporting Resources Staging Testing Time Topotecan Toxic effect Weight Work aldehyde dehydrogenases base cancer therapy chemotherapy clinical efficacy clinical phenotype combinatorial cytotoxic cytotoxicity experience high risk human NAT2 protein improved outcome forecast public health relevance resistance mechanism response success tumor

项目摘要

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.

描述（由申请人提供）：这项工作的远距离目标是通过通过药物遗传学个性化癌症治疗和/或环磷酰胺（CY）剂量来改善新诊断的高危神经母细胞瘤儿童的整体生存期。 CY是大多数儿科癌症患者的初始治愈性化疗方案的重要组成部分。当前按身体表面积或体重给予Cy的方法导致系统性暴露的大量室内变异性，在血浆浓度时曲线（AUC）下，Cy及其代谢产物表示为面积。暴露于4-羟环磷酰胺（4HCY）的变异性是Cy的细胞毒性代谢产物的主要前体，可能是CY疗效的室内差异。我们的工作假设是，参与4HCY的生产和消除的酶和转运蛋白的多态性与4HCY/CY AUC的较高比率相关，提高了诱导响应率，从而改善了事件的无生存率。我们将检验以下假设：与新诊断出的高风险神经细胞瘤的儿童中，参与生产和消除4HCY的药物代谢酶和参与4HCY的转运蛋白与对剂量敏感拓扑替康/环磷酰胺（拓扑）诱导方案的反应有关。该目标将作为一项与III期儿童肿瘤学组试验ANBL0532的相关研究完成，该试验于2012年2月完成了应计。我们从380 ANBL0532参与者中收集了生殖线DNA，所有这些参与者都接受了相同的诱导化疗方案，用于两次cycles toce cycles of Multi-agent Chement of Mugagent of-Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent of Agagent。对Topocy的诱导反应是主要终点，而3年无事件生存是次要终点。在具有高危神经母细胞瘤的患者中，诱导反应与整体生存有关，因此，最大化诱导反应将改善总体生存率。使用候选基因方法，我们确定了22种调节参与4HCy形成的酶，调节酶或涉及4HCY消除的酶或转运，或调节与结果相关的蛋白质，但显然与4HCY Pharmacokinetics相关，但与其他与其他癌症患者相关的蛋白质，但显然与其他癌症患者相关。我们试图评估这些候选基因中的多态性是否与托托环节诱导反应率和3年无事件生存有关，其长期目标是改善高风险神经母细胞瘤儿童的总体生存。该提案非常适合NCI计划公告（PAR-12-144），因为该赠款建议对现有数据进行二次分析，以提出基于CY-基于CY-基于组合治疗和患者预后的改进和评估。