Pharmacokinetics and pharmacogenomics for 13-cis retinoic acid in neuroblastoma

描述（申请人提供）：神经母细胞瘤是儿童交感神经系统的恶性肿瘤。13-顺式维甲酸（13-顺式ra）可诱导人神经母细胞瘤细胞分化，高剂量、脉冲13-顺式ra治疗可显著提高高危神经母细胞瘤患者的总生存率，但许多儿童在13-顺式ra治疗期间或治疗后出现复发。作为儿童肿瘤组（COG）的类维生素a药理学实验室，我们一直在收集神经母细胞瘤（A-3973, ANBL0532， ANBL0032和ANBL0931）的多个III期临床试验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13-顺式ra浓度（< 5 μ M），而13-顺式ra代谢物4-氧-13-顺式ra在约44%的患者中为5 μ M。其他研究者推测，4-氧-13-顺- ra是一种无活性代谢物，一些人建议调节13-顺- ra的代谢，以防止药物转化为4-氧-13-顺- ra，从而潜在地提高药物的临床活性

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.