Related Experiment Video
Updated: Apr 11, 2026
Zebrafish Model of Neuroblastoma Metastasis
Published on: March 14, 2021
A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma
Giselle L Saulnier Sholler1, Eugene W Gerner2, Genevieve Bergendahl3
1Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States of America; College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America.
Background:
Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.
Methods And Findings:
Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).
Conclusions:
DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.
Trial Registration:
Clinicaltrials.gov NCT#01059071.
Insights
Difluoromethylornithine (DFMO) is safe for treating relapsed neuroblastoma in children. Patients with a specific ODC gene variant showed better response and longer progression-free survival, suggesting a targeted therapy approach.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Genetics
Background:
- Neuroblastoma (NB) is a leading cause of childhood cancer death.
- Ornithine decarboxylase (ODC) expression correlates with poor NB prognosis.
- Investigating ODC inhibitors like DFMO for relapsed/refractory NB is crucial.
Purpose of the Study:
- To evaluate the safety and efficacy of difluoromethylornithine (DFMO) ± etoposide in pediatric patients with relapsed or refractory neuroblastoma.
- To explore pharmacokinetic, genetic, and metabolic factors influencing treatment response.
Main Methods:
- Phase I clinical trial involving 21 pediatric patients with relapsed/refractory NB.
- Oral administration of DFMO (500-1500 mg/m²/day) alone and in combination with etoposide.
- Measurement of DFMO pharmacokinetics, ODC gene single nucleotide polymorphisms (SNPs), and urinary polyamine levels.
Main Results:
- DFMO doses up to 1500 mg/m²/day were safe and well-tolerated, with no dose-limiting toxicities observed.
- Patients with the ODC rs2302616 minor T-allele exhibited higher baseline polyamine levels and greater polyamine reduction during DFMO therapy.
- A trend towards longer progression-free survival was noted in patients with the T-allele and those with lower baseline urinary polyamines.
Conclusions:
- DFMO is a safe and tolerable treatment option for children with relapsed NB.
- The ODC rs2302616 genotype may identify a subset of NB patients who benefit more from DFMO-containing therapies.
- Targeting the polyamine pathway with DFMO shows promise for specific neuroblastoma patient populations.
