The Next Frontier in Sarcoma: Molecular Pathways and Associated Targeted Therapies

SIMPLE SUMMARY: Soft tissue sarcomas are an extremely rare group of cancers from mesenchymal origin. STS are difficult to treat due to their large variety of histological subtypes that dictate both their individual tumorigenesis and clinical characteristics. Although traditional chemotherapy has remained the mainstay treatment for advanced and metastatic disease, targeted therapies have emerged as a promising new approach to treat STS based on the specific molecular pathways of the tumor. Further elucidating the molecular pathways implicated in the development of STS will help guide the development of promising new therapeutics that can effectively target these pathways. Numerous targeted therapies against STS are therefore being tested in clinical studies to evaluate the efficacy and safety of these new treatments. ABSTRACT: Soft tissue sarcomas (STS) are a rare, complex, heterogeneous group of mesenchymal neoplasms with over 150 different histological subtypes. Treatments for this malignancy have been especially challenging due to the heterogeneity of the disease and the modest efficacy of conventional chemotherapy. The next frontier lies in discerning the molecular pathways in which these mesenchymal neoplasms arise, metastasize, and develop drug-resistance, thereby helping guide new therapeutic targets for the treatment of STS. This comprehensive review will discuss the current understanding of tumorigenesis of specific STS subtypes, including oncogenic pathway alterations involved in cell cycle regulation, angiogenesis, NOTCH signaling, and aberrant genetic rearrangements. It will then review current therapies that have been recently developed to target these pathways, including a review of ongoing clinical studies for targeted sarcoma treatment, as well as discuss new potential avenues for therapies against known molecular pathways of sarcomagenesis.