Characterization of the metabolic profile and identification of potential therapeutic targets in advanced prostate cancer patients

Resumen

Prostate cancer (PCa) is the second most frequently diagnosed cancer and represents the fifth leading cause of death in male. PCa is a hormone-dependent tumor characterized by an extremely variable clinical course, ranging from an indolent condition to a rapid progression into an aggressive phenotype that disseminates and metastasizes. Optimal management of PCa patients remains challenging due to the difficulties in accurately predicting and discriminating indolent patients from those that may develop aggressive and metastatic progression. Nevertheless, despite the great advances made in biomarker discovery, very few are actually being used in the clinical practice, and there is still a need for more precise and robust biomarkers to improve the diagnosis and risk stratification of PCa patients. On the other hand, despite the efforts made in developing new therapeutic strategies for PCa treatment, the disease remains incurable when it progresses to more aggressive stages. Thus, the development of new treatments to avoid the unwanted side-effects caused by currently available therapies, increase the overall survival rate and improve life quality of patients diagnosed with aggressive PCa tumors is highly needed. In this context, different omics-based approaches have shown great potential for the development of novel targeted therapies as well as for the identification of non-invasive prognostic biomarkers. The present work aims to characterize metabolic changes related to PCa progression, and identify specific genetic vulnerabilities in advanced PCa. In the first objective, the integrated analysis of metabolic changes observed locally (tissue) and systemically (serum and urine) has revealed dysregulations in the nucleotide synthesis and energy metabolism of high-grade PCa patients. At the transcriptomic level, these patients have showed increased purine biosynthesis resulted from an enhanced folate cycle, together with a slow glycolysis rate that may be balanced by an enhanced OXPHOS activity. These alterations are reflected, at the systemic level, by elevated glycine and glucose serum levels and increased urine levels of 1-methylnicotinamide in these same patients. On the other hand, the combination of essentiality analyses together with differential expression and disease progression analyses, based on transcriptomic data, has been proved to be an effective approach for the identification of novel potential therapeutic. Among the most promising candidates identified following this strategy, the role of EIF3H as a potential target in advanced PCa stages has been validated. In particular, EIF3H inhibition significantly diminishes proliferation, colony formation and migration capacity of PC3 cells, while its over-expression while opposite results are observed in the over-expression model. In addition, changes in EIF3H levels promote the epithelial-mesenchymal transition, therefore, suggesting potential role in regulating this process in PC3 cells.