MDA-9/Syntenin as a therapeutic cancer metastasis target: current molecular and preclinical understanding

Introduction: Metastasis is a principal cause of patient morbidity and death from solid cancers with current therapies being inadequate. Areas Covered: Detailed genomic analyses document mutational differences between the initial tumor and metastatic clones, posing a challenge to current targeted therapies, which focus predominantly on the phenotype of primary tumors. Considering the diverse signaling cascades and numerous compensatory pathways in metastasis, designing broad-spectrum anti-metastatic therapies remains challenging. Although significant anti-cancer activity is evident in specific patients with advanced cancers and metastases treated with single or combination immunotherapies, there are limitations, i.e. toxicity, immune inhibitory 'cold' tumors and the tumor microenvironment (TME), and intra- and intertumoral heterogeneity. Accordingly, multidisciplinary strategies are required to attack metastases and the TME to obtain optimal therapeutic responses. Expert Opinion: To create potent anti-metastatic agents, defining critical genes/proteins and drugs controlling discrete steps in the metastatic cascade are mandatory. Melanoma differentiation-associated gene-9 (MDA-9), Syndecan Binding Protein (SDCBP) or Syntenin (MDA-9/Syntenin) is robustly expressed and serves essential roles in cancer disease progression through protein-protein interactions with additional metastasis-associated molecules and pathways. The importance of MDA-9/Syntenin in the metastatic process is now established and first-in-class inhibitory molecules look promising with some moving toward clinical evaluation.