Pharmacokinetics and pharmacogenomics for 13-cis retinoic acid in neuroblastoma

描述(申请人提供)：神经母细胞瘤是一种儿童交感神经系统的恶性肿瘤。13-顺式维甲酸(13-cis-RA)可诱导人神经母细胞瘤细胞分化，大剂量脉冲13-cis-RA治疗显著提高了高危神经母细胞瘤患者的总体生存率，但许多儿童在13-cis-RA治疗过程中或治疗后出现复发。作为儿童肿瘤组(COG)的维甲酸药理实验室，我们一直在收集神经母细胞瘤多期临床试验(A-3973、ANBL0532、ANBL0032和ANBL0931)的血浆样本和细胞颗粒。出乎意料的是，在370名患者中，95%的患者达到了临床前研究预测的亚治疗13-顺式维甲酸的浓度(&lt；5�M)，而约44%的患者的13-顺式维甲酸代谢产物4-氧代-13-顺式维甲酸的浓度为5�M。其他研究人员推测，4-oxo-13-cis-RA是一种非活性代谢物，一些人建议调节13-cis-RA的代谢，以防止药物转化为4-oxo-13-cis-RA，从而潜在地改善 毒品。相反，我们的初步实验表明，4-oxo-13-cis-RA在激活维甲酸信号、抑制细胞增殖和下调神经母细胞瘤细胞MYCN方面与母药一样有效。这些新的观察结果导致了我们的假设：1)达到e5�M13-cis-RA和/或4-oxo-13-cis-RA的血浆浓度是13-cis-RA治疗结果的重要决定因素。2)患者的13-顺式维甲酸药代动力学(PK)变异与酶基因多态性(药物基因组学：PG)相关。3)治疗结果将确定PG信息的作用，并验证13-cis-RA和/或4-oxo-13-cis-RA的目标水平，使未来PK/PG引导的13-cis-RA剂量成为可能。13-顺式维甲酸的全身毒性有利于今后的剂量调整研究，特别是如果 目前推定的靶药物水平可以通过临床结果数据来验证，这样PK/PG数据就可以用来确定低药物水平(亚治疗)和非常高药物水平(可能的全身毒性)患者队列的最佳剂量。我们建议1)在参加III期临床试验的600名高危神经母细胞瘤患者的样本中研究13-顺式维甲酸的药代动力学和代谢特征；2)使用需要最少神经母细胞瘤患者gDNA样本的快速吞吐量筛选方法来确定酶多态的PG；3)并证明13-顺式维甲酸的PK和/或PG与接受13-顺式维甲酸治疗的神经母细胞瘤患者的临床结果相关。这项拟议的研究可能会确定PK和/或PG参数，这些参数可用于优化13-顺式维甲酸在高危神经母细胞瘤患者中的剂量。

DESCRIPTION (provided by applicant): Neuroblastoma is a malignant childhood tumor of the sympathetic nervous system. 13-cis retinoic acid (13- cis-RA) induces differentiation of human neuroblastoma cells, and high-dose, pulse 13-cis-RA treatment significantly improves overall survival of high-risk neuroblastoma patients, but many children develop recurrent disease during or after 13-cis-RA treatment. As the retinoid pharmacology laboratory for the Children's Oncology Group (COG), we have been collecting plasma samples and cell pellets from multiple phase III clinical trials of neuroblastoma (A-3973, ANBL0532, ANBL0032, and ANBL0931). Unexpectedly, 95% of 370 patients achieved concentrations (< 5 �M) of 13-cis-RA predicted to be subtherapeutic by preclinical studies, while the 13-cis-RA metabolite 4-oxo-13-cis-RA was e 5 �M in about 44% of patients. Other investigators have speculated that 4-oxo-13-cis-RA is an inactive metabolite and some have suggested modulation of 13-cis-RA metabolism to prevent transformation of the drug into 4-oxo-13-cis-RA to potentially improve the clinical activity of the drug. By contrast, our preliminary experiments revealed that 4-oxo-13-cis- RA is as active as the parent drug in activation of retinoid signaling, inhibition of cell proliferation, and MYCN down-regulation in neuroblastoma cells. These novel observations led to our hypotheses that: 1) Achieving a plasma concentration of e 5 �M 13-cis-RA and/or 4-oxo-13-cis-RA is an important determinant of treatment outcome of 13-cis-RA. 2) 13-cis-RA pharmacokinetic (PK) variations seen in patients are associated with enzymatic polymorphisms (pharmacogenomics: PG). 3) Treatment outcomes will define the role of PG information and validate target levels of 13-cis-RA and/or 4-oxo-13-cis-RA, enabling future PK/PG-guided dosing of 13-cis-RA. Systemic toxicities of 13-cis-RA are favorable to entertaining future dose-adjustment studies, especially if currently presumed target drug levels could be validated by clinical outcome data so that PK/PG data can be used to determine optimal dosing for low drug level (subtherapeutic) and very high drug level (possible systemic toxicity) patient cohorts. We propose 1) to study pharmacokinetic and metabolic profiling of 13-cis-RA in samples from 600 high-risk neuroblastoma patients enrolled in phase III clinical trials; 2) to determine PG of enzymatic polymorphisms using rapid throughput screening methods requiring minimal amounts of gDNA samples of neuroblastoma patients; 3) and to demonstrate that PK and/or PG for 13-cis- RA correlates with clinical outcomes for neuroblastoma patients undergoing 13-cis-RA treatment. This proposed study will potentially define PK and/or PG parameters that can be used to optimize dosing of 13- cis-RA in high-risk neuroblastoma patients.