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.

Public Health Relevance

The goal of these studies is to improve a child's chance of survival when (s)he receives a commonly used anti-cancer drug called cyclophosphamide. We will see if certain genes relate to how well a child with newly diagnosed high-risk neuroblastoma responds to two cycles of cyclophosphamide combined with topotecan.

National Institute of Health (NIH)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1)
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Thurin, Magdalena
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University of Washington
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Schools of Pharmacy
United States
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