Abstract 5832: Overexpression of ODC1 is associated with poor outcome in childhood neuroblastoma and represents an important therapeutic target

Abstract

Abstract MYCN gene amplification is a powerful predictor of poor clinical outcome in neuroblastoma, the most common solid tumor of young children. The mechanism by which MYCN amplification influences the prognosis of this disease has not been well defined. MYCN is a known transcription factor and available evidence indicates that ornithine decarboxylase (ODC1) is a critical downstream target for this oncoprotein. ODC1 is the rate-limiting enzyme in the synthesis of polyamines and overexpression of this gene has been observed in a range of tumor cells, including neuroblastoma. In particular, a number of studies have provided evidence for the oncogenic and transforming abilities of ODC1. To investigate the role of ODC1 in neuroblastoma, we used Real-Time PCR to analyze ODC1 expression in a large cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in this cohort. ODC1 expression was significantly higher in MYCN-amplified tumors by comparison with non-amplified tumors (p<0.0001). Kaplan-Meier survival analysis indicated that high levels of ODC1 expression were strongly predictive of both event-free-survival (p<0.001) and overall survival (p<0.001) in this cohort as well as in patients whose tumors lacked MYCN amplification (p=0.01). Furthermore, a functionally important single nucleotide polymorphism within the ODC1 promoter (G316A) that has been shown previously to influence gene transcription rates, was found to be significantly associated with outcome in patients whose tumors lacked MYCN amplification (p<0.05). These data suggest that inhibiting ODC1 activity would have therapeutic advantage in treating neuroblastoma. To test this hypothesis, MYCN transgenic mice that spontaneously develop neuroblastoma closely mimicking the human disease, were treated either with cisplatin alone or in combination with the ODC1 inhibitor, α-difluoromethylornithine (DFMO). Importantly, DFMO therapy, either concomitant with or following cisplatin treatment, resulted in prolonged tumor-free survival (p<0.01) in these mice, by comparison with cisplatin administered alone. Similar results were obtained with cyclophosphamide treatment in combination with DFMO. No overt toxicity attributable to DFMO therapy was noted in treated mice. Collectively, these findings provide strong evidence that ODC1 contributes to the malignant phenotype of neuroblastoma and suggest that targeting this oncogene for suppression of polyamine synthesis is potentially a valuable therapeutic approach for inhibiting neuroblastoma growth.