Pharmacokinetics and pharmacogenomics for 13-cis retinoic acid in neuroblastoma

描述（由申请人提供）：神经母细胞瘤是一种儿童交感神经系统恶性肿瘤。13-顺式维甲酸（13- cis-RA）诱导人神经母细胞瘤细胞分化，高剂量、脉冲13-cis-RA治疗显著改善高危神经母细胞瘤患者的总体存活率，但许多儿童在13-cis-RA治疗期间或之后发生复发性疾病。作为儿童肿瘤组（COG）的维甲酸药理学实验室，我们一直在收集来自神经母细胞瘤多项III期临床试验（A-3973、ANBL 0532、ANBL 0032和ANBL 0931）的血浆样本和细胞团。出乎意料的是，370例患者中有95%达到了临床前研究预测的亚治疗浓度（< 5 <$M）的13-cis-RA，而13-cis-RA代谢物4-oxo-13-cis-RA在约44%的患者中为5 <$M。其他研究者推测4-氧代-13-顺式-RA是无活性代谢物，并且一些研究者建议调节13-顺式-RA代谢以防止药物转化为4-氧代-13-顺式-RA，从而潜在地改善药物的临床活性。 药相比之下，我们的初步实验表明，4-氧代-13-顺式- RA在神经母细胞瘤细胞中激活类维生素A信号传导、抑制细胞增殖和MYCN下调方面与母体药物一样有活性。这些新的观察结果导致我们的假设：1）达到5 μ M 13-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)在患者中观察到的13-顺式-RA药代动力学（PK）变化与酶多态性相关（药物基因组学：PG）。3)治疗结局将定义PG信息的作用，并验证13-cis-RA和/或4-oxo-13-cis-RA的目标水平，从而实现13-cis-RA的未来PK/PG指导给药。13-cis-RA的全身毒性有利于将来进行剂量调整研究，特别是如果 目前假定的目标药物水平可以通过临床结果数据来验证，使得PK/PG数据可以用于确定低药物水平（亚治疗）和非常高药物水平（可能的全身毒性）患者群组的最佳剂量。我们建议1）在来自600名参加III期临床试验的高危神经母细胞瘤患者的样品中研究13-cis-RA的药代动力学和代谢谱; 2）使用快速通量筛选方法确定酶多态性的PG，所述方法需要最少量的神经母细胞瘤患者的gDNA样品; 3）并证明13-顺式- RA的PK和/或PG与接受13-顺式-RA治疗的神经母细胞瘤患者的临床结果相关。这项拟议的研究将可能定义PK和/或PG参数，可用于优化高危神经母细胞瘤患者中13- cis-RA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.