Exploring polyamine biosynthesis as a therapeutic vulnerability in medulloblastoma
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 20% of all childhood cancers. Standard-of-care therapy of MB includes surgery, radiation and chemotherapy. These therapies are highly toxic, poorly tolerated in children, and may result in neurocognitive deficits and an increased risk of secondary cancers. There is thus an unmet need for more effective and less toxic treatments. Polyamines are downstream products of the urea cycle involved in cell differentiation, survival, and proliferation. Increased levels of polyamines have been reported in several cancers, including MB. In particular, altered polyamine metabolism has been reported in Sonic-Hedgehog (SHH) MB. Our preliminary studies have shown a partial reduction in malignant cell viability upon treatment with either α-difluoromethylornithine (DFMO) or Sardomozide (polyamine biosynthesis inhibitors) in the DAOY SHH MB cell line. We hypothesized that targeting polyamine biosynthesis would alter the cellular metabolome, which may sensitize MB cells to standard-of-care chemotherapy treatments. Metabolic profiling of DAOY cells treated with DFMO and Sardomozide showed a decrease in polyamines and an increase in argininosuccinate and metabolites of glycolysis, the TCA cycle, and oxidative phosphorylation compared to the untreated control. However, product-to-substrate ratios representing aerobic glycolysis and oxidative phosphorylation were decreased upon treatment. This may point to polyamine inhibitors having a cytostatic effect. Our findings suggest that DFMO and Sardomozide may be channeling urea cycle metabolites towards energy production; this outcome will be validated using functional metabolic assays. Additionally, the combination treatment of DFMO and Etoposide (chemotherapeutic agent) exhibited synergy at 254.9 nM, lowering the IC50 dose of Etoposide by ~20 nM. This could translate to a lower chemotherapeutic dose, directly reducing treatment toxicities and improving patient outcomes. Further investigation is required to understand the mechanisms driving drug synergy and its impact on the MB metabolome.
