Novel therapeutic approaches to high-risk neuroblastoma targeting cancer metabolism

Abstract

The current results of treatment strategies for high-risk neuroblastoma have been far from satisfactory. ALK inhibitors were greatly anticipated to cure this disease, but practically, a large proportion of the patients did not benefit from them. A new approach is required to make advances. Reprogramming of metabolism in cancer cells, also called cancer metabolism, has been recognized as an important hallmark of malignancy, as it is deeply related to tumor progression and treatment resistance. We analyzed several datasets of neuroblastoma including our institutional cohort and extracted PHGDH, which is the gene encoding phosphoglycerate dehydrogenase (PHGDH), as a candidate target gene, a high expression level of which correlates with poor prognosis in these multiple cohorts. PHGDH is the enzyme essential in serine metabolism, and the enhancement of its expression has been observed in several other malignancies. We further conducted functional analyses in vitro and confirmed that the inhibition of PHGDH suppressed cell growth in neuroblastoma cells with a high PHGDH expression level. Also, by conducting metabolome and transcriptome analyses, we found that arginine depletion by the prior administration of arginine deiminase enhanced the cytotoxic effect of the PHGDH inhibitor in a subset of neuroblastoma cells by altering cellular metabolism. In summary, our results suggest that manipulating cancer metabolism is a powerful approach to developing novel therapeutic strategies against aggressive neuroblastoma.