Combined Dietary and Pharmacological Depletion of Polyamines Targets Oncogenic Translation in Neuroblastoma
Cancer growth is fueled by nutrients obtained from circulation and local biosynthesis. Isolating and exploiting tumoral nutrient dependencies to potentiate current anti-cancer therapies is undergoing active research. We used unbiased metabolomics on patient samples and identified reprogramming of the arginine-proline-glutamine axis in MYCN amplified neuroblastoma. Tumoral acquisition of these non-essential amnio acids, as revealed by stable isotope tracing, was primarily by import, while extra-tumoral deamination of arginine indirectly feeds tumor ornithine via circulation. Dietary depletion of proline and arginine reduced systemic ornithine, the direct precursor of polyamine biosynthesis, and in combination with the clinically approved polyamine biosynthesis inhibitor, difluoromethylornithine, enhanced their depletion to improve survival in a MYCN-driven neuroblastoma mouse model. Mechanistically, ribosome profiling indicated specific translation defects, with ribosomal pausing at adenine-ending codons, to cause reprogramed protein biosynthesis affecting cell cycle and inducing neuronal differentiation. This work provides proof of concept for combined small molecule and nutrient depletion therapy for simultaneous targeting of translation in cancers dependent on external nutrient uptake. Overall design: Assessment of translation of tumors through ribosome profiling and transcriptomics. Each sample are taken from tumor found from TH-MYCN mice under pharmacological and dietary intervention. Each sample represents a different mouse. Control samples are the mice with a defined control diet (CD) and no pharmacological treatment.