Combining Antiangiogenic Drugs with Vascular Disrupting Agents Rationale and Mechanisms of Action

Abstract

A highly reproducible characteristic of vascular disrupting agent (VDA)-mediated anti-tumor therapy is the retention of a rim of viable tumor tissue surrounding a much larger central mass of necrotic tissue within days of therapy. Repopulation from the viable rim subsequently compromises much of the striking initial anti-tumor effect frequently caused by the VDA treatment. The repopulation process is driven in part by robust tumor angiogenesis, which therefore constitutes a compelling rationale for combining VDA therapy with an antiangiogenic drug. In this regard, we have found that tumor angiogenesis in the viable rim after VDA therapy can be driven, at least in part, by a rapid systemic host response caused by the VDA treatment itself, namely, induction within hours of the mobilization of bone marrow-derived cells (BMDCs) including circulating endothelial progenitor cells (CEPs). These cells migrate to the drug treated tumor and heavily colonize the remaining viable tumor rim. This systemic host response appears to be driven, at least in part, by rapid induction of high levels of circulating growth factors, including G-CSF and SDF-1. The mobilization and tumor homing of CEPs can be blunted by prior or concurrent administration of an antiangiogenic drug such as anti-VEGF receptor 2 antibodies – which results in enhanced overall anti-tumor activity, e.g. greater levels of tumor necrosis, a much smaller viable tumor rim and increased survival times. In addition to this systemic effect, a more potent ‘local’ effect may also be obtained by adding an antiangiogenic drug to a VDA as a result of greater levels of apoptosis of endothelial cells in the tumor associated vasculature. Preliminary clinical trial results suggest combination VDA – antiangiogenic drug therapy has promising activity without significant increases in toxicity, and moreover, indicate that some of the preclinical findings, such as rapid VDA-induced elevations of circulating G-CSF and VEGF, are observed in patients as well.