Diagnostic and Therapeutic Targets in Cartilaginous Tumours

This study, "Finding new diagnostic and therapeutic targets in cartilaginous tumours," focuses on improving the diagnosis, prognostic stratification, and treatment options for chondroid tumours, particularly chondrosarcoma. Chondrosarcoma is the most common primary malignant bone tumour in adults and is characterized by resistance to chemotherapy and radiotherapy, making accurate diagnosis and optimal surgical management critical. Distinguishing benign cartilage tumours (enchondromas, atypical cartilaginous tumours) from low-grade chondrosarcoma, and differentiating chondrosarcoma from chondroblastic osteosarcoma, remain major diagnostic challenges.

The project investigates two key molecular markers: mutations in IDH1/2 genes and non-coding microRNAs (miRNAs). IDH1/2 mutations are frequent in central chondrosarcomas and rare in other mesenchymal tumours, making them promising diagnostic markers. Their presence may also have prognostic significance and therapeutic relevance, as IDH inhibitors are already available for other malignancies. In parallel, deregulated miRNA expression has been implicated in chondrosarcoma biology, influencing tumour growth, invasion, angiogenesis, metastasis, and chemosensitivity. Preliminary data identified distinct miRNA signatures in chondrosarcoma compared with healthy cartilage, including previously unreported miRNAs.

The study is structured into exploratory and validation phases. Global miRNA expression profiling and IDH1/2 mutation analysis will be performed using next-generation sequencing (NGS) on prospectively collected fresh-frozen tumour samples. Selected miRNAs and IDH1/2 mutation status will then be validated by RT-qPCR and targeted mutation assays in a large retrospective cohort of FFPE samples. Molecular data will be integrated with clinicopathological parameters to develop diagnostic panels capable of accurately classifying chondroid tumours, as well as prognostic miRNA panels associated with patient survival.

Additionally, the project evaluates circulating and exosomal miRNAs in liquid biopsies, aiming to establish non-invasive diagnostic and prognostic tools. Functional relevance will be explored using chondrosarcoma cell lines with simulated miRNA upregulation, coupled with transcriptomic analysis.

Overall, the study seeks to refine diagnostic accuracy, improve prognostic assessment, and identify novel molecular targets for personalized and targeted therapy in patients with inoperable or metastatic chondrosarcoma, addressing a major unmet clinical need.