Multiomics profiling toward a precision medicine approach to rare diseases

Precision medicine aims to improve diagnosis and treatment by taking into account the molecular and biological differences between patients. This approach is especially important for complex and rare diseases, such as cancer and inherited metabolic disorders, where standard therapeutic strategies often fail to fully address disease heterogeneity and variability in treatment response. Recent advances in omics technologies have made it possible to study biological systems at multiple levels, offering new opportunities to identify biomarkers and better understand disease mechanisms. In this context, a multi-omics approach provides a powerful tool for capturing biochemical changes associated with complex diseases, particularly in rare disorders and cancers with high biological heterogeneity. In this thesis, an integrated approach based on NMR metabolomics, genomic analysis, and molecular biology was used to study cancer and a rare metabolic disease. Soft Tissue Sarcomas (STS), Bladder Cancer (BC), and Ovarian Cancer (OC) were analysed to identify common molecular features. NMR-based metabolomics showed major changes in energy metabolism in all three cancers. In addition, the accumulation of hypoxanthine pointed to altered purine metabolism, revealing a common vulnerability in the purine salvage pathway that may be useful for disease classification and treatment. These metabolic changes were also connected to genetic defects. At the molecular level, NMR structural studies of the Y-box binding protein 1 Cold Shock Domain (YB1 CSD) showed that phosphorylation at Serine 102 by the RSK4 kinase can only occur when the protein is bound to DNA. This finding highlights the importance of protein structure in cancer signalling. Finally, the clinical value of metabolomics was demonstrated in Alkaptonuria (AKU). Long-term NMR monitoring of patients treated with nitisinone clarified changes in the tyrosine pathway and supported safe, non-invasive treatment monitoring.