Therapeutic opportunity of phosphodiesterase 3A modulators in myxoid liposarcomas

Liposarcoma is a common soft tissue sarcoma, and is classified into four histological subtypes, each with distinct disease outcome, morphology, and genotype. Typical primary treatment in advanced liposarcoma consists of surgery, combined with chemotherapy, radiotherapy, or both. There are currently no approved targeted therapeutics or precision medicine opportunities in liposarcoma. Here we investigated 131 liposarcoma tumour samples by transcriptional profiling and 543 sarcomas by immunoprofiling and compared these data with high-throughput drug sensitivity testing in liposarcoma cell lines in vitro. The data showed that i) myxoid liposarcomas, specifically the high-grade phenotype, display high levels of PDE3A gene expression and that ii) PDE3A modulators are effective inhibitors in PDE3A and SLFN12 co-expressing soft tissue sarcoma cell lines. iii) In addition, PDE3A modulators synergize with many emerging targeted therapies and sensitize sarcoma cell lines to Bcl-2 family inhibitors. We suggest that overexpression of PDE3A and SLFN12 genes is common in myxoid liposarcomas and that this leads to sensitivity to PDE3A modulators and synergy with Bcl-2 family inhibition. Further studies are warranted to translate these observations into precision liposarcoma therapy.