Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy

Genomic-based precision medicine has not only improved tumour therapy but has also shown its weaknesses. Genomic profiling and mutation analysis have identified alterations that play a major role in sarcoma pathogenesis and evolution. However, they have not been sufficient in predicting tumour vulnerability and advancing treatment. The relative rarity of sarcomas and the genetic heterogeneity between subtypes also stand in the way of gaining statistically significant results from clinical trials. Personalized three-dimensional tumour models that reflect the specific histologic subtype are emerging as functional assays to test anticancer drugs, complementing genomic screening. Here, we provide an overview of current target therapy for sarcomas and discuss functional assays based on 3D models that, by recapitulating the molecular pathways and tumour microenvironment, may predict patient response to treatments. This approach opens new avenues to improve precision medicine when genomic and pathway alterations are not sufficient to guide the choice of the most promising treatment. Furthermore, we discuss the aspects of the 3D culture assays that need to be improved, such as the standardisation of growth conditions and the definition of in vitro responses that can be used as a cut-off for clinical implementation.