Pharmacokinetics and pharmacogenomics for 13-cis retinoic acid in neuroblastoma

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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.