Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy

Purpose: Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment. Experimental Design: Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins. Results: The three agents alone were shown to significantly inhibit endothelial cells9 ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay ( P P P Conclusions: This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.