Genomewide therapeutic target screens in novel preclinical models of liposarcoma
Liposarcoma is one of the most common soft-tissue sarcomas, with well-differentiated/dedifferentiated liposarcoma subtype forming the majority of cases. Although recurrences are frequent, surgery remains the mainstay of treatment when feasible due to the limited role of currently available systemic treatments. Response rates to front line sarcoma regimens like doxorubicin or gemcitabine-based combinations are reported to be 20% or less, dropping further for therapies in the later lines. Reliable preclinical models help accelerate the pace of development of newer therapies as they can identify agents with a higher likelihood to succeed in the clinical setting. This helps increase our ability to perform smaller subtype specific trials and decreases the burden of large negative clinical studies in a rare disease. Patient-derived cell lines (2D) don’t translate well to the clinical setting and while xenografts are closer to the primary tumor they demand significant time and resources. Tumor organoids as a 3D cell culture has been shown to be superior to 2D in terms of establishment rate and preserving characteristics of the tumor of origin, for example, cell differentiation, heterogeneity, structure and morphology, and cell-cell and cell-extracellular matrix interactions. The model also provides opportunities to screen many drugs in varying conditions an the same time with greater accuracy. Limited publications have described organoid studies in sarcoma. Reports on successful 3D organoids generation in Ewing’s sarcoma and synovial sarcoma revealed concordant benefits as previously documented in carcinomas. We will establish and characterize a 3D well-differentiated/dedifferentiated liposarcoma organoid model for the first time and identify new potential treatments through high-throughput drug screening. Development of a liposarcoma organoid model will provide an efficient way to further study tumor biology, relevant pathways, and potential drug candidates in the future.