Tasquinimod prevents the angiogenic rebound induced by fractionated radiation resulting in an enhanced therapeutic response of prostate cancer xenografts

BACKGROUND Tasquinimod is a novel inhibitor of tumor angiogenesis which enhances therapeutic efficacy when combined with androgen ablation and/or taxane-based chemotherapies in pre-clinical prostate cancer models. It has entered registration Phase III evaluation for the treatment of castration resistant prostate cancer. Since tasquinimod suppresses the angiogenic switch induced by tumor hypoxia as prostate cancers outgrow their blood supply, this raises the issue of whether tasquinimod also suppresses the angiogenic rebound induced by fractionated radiation thereby enhancing therapeutic response to fractionated radiation. METHODS Human endothelial and prostate cancer cells in culture and human prostate cancer xenografts growing in castrated male nude mice were evaluated for their response to radiation alone and in combination with tasquinimod. RESULTS At clinically relevant drug levels, tasquinimod significantly (P<0.05) enhances anti-cancer efficacy of fractionated radiation with optimal timing for initiating daily tasquinimod treatment being after completion of the fractionated radiation. CONCLUSIONS Based upon cell culture studies and tumor tissue oxygenation (i.e., pO ₂), tumor vascular volume, and tumor blood vessel density measurements, the mechanism for such enhancement and optimal timing involves tasquinimod's ability to prevent the angiogenic rebound induced by fractionated radiation.