Abstract A04: Is the lack of clinical success with antiangiogenic therapy due to vascular normalization not being a universal phenomenon?
Authors: Horsman Michael R. , Siemann Dietmar W. 
Published: December 2015

Abstract
Introduction: Pre-clinical studies have demonstrated that combining angiogenesis inhibitors (AIs) with conventional radiation and chemotherapy treatments can be an effective anti-tumor therapy. However, clinical benefits from such combinations have been more modest. A principal mechanism by which AIs are believed to increase tumor sensitivity to radiation and chemotherapy is vascular normalization, a process which should improve tumor blood perfusion and oxygenation. Here we review the universality of this concept by examining those pre-clinical studies that directly determined the effect of AI treatment on tumor oxygenation.
Methods: This review was based on searching the PubMed database using the criteria angiogenesis inhibitors combined with one of each of the following: oxygenation, hypoxia, or normalization coupled with our own knowledge within the fields of tumor hypoxia and vascular targeting. A total of 51 pre-clinical studies were identified. The techniques used to monitor hypoxia/oxygenation included immunohistochemical analysis of hypoxia marker binding (pimonidazole and EF5) or hypoxia gene expression (CA9 and HIF-1alpha), direct oxygenation measurements (Eppendorf electrode, EPR oximetry, Oxylite probe or phosphorous quenching), or radiation response. The AIs included the two principal classes of inhibitors, those targeting VEGF (bevacizumab, DC101) and tyrosine kinase (vandetanib, sunitinib, sorafanib, axitinib, pazopanib, AG-013736, PTK787/ZK222584, SU5416), as well as a variety of other agents (TNP-470, suramin, endostatin, thrombospondin, thalidomide, anginex, arginine deiminase, nucleolin antagonist, nelfinavir).
Results: 19 studies demonstrated significant improvements in tumor oxygenation status. These included a decrease in hypoxia marker labelling (bevacizumab, DC101, suramin, endostatin, nucleolin antagonist); an increase in oxygenation determined using the Eppendorf electrode (TNP-470 and an anti-VEGF antibody), EPR oximetry (thalidomide, vandetanib, SU5416), and Oxylite probe (bevacizumab); an increase in hypoxia regulated gene expression (endostatin and SU5416); and enhanced radiation response (thrombospondin). In contrast, 21 studies found a significant decrease in tumor oxygenation using hypoxic markers measured by immunohistochemistry (bevacizumab, DC101, sunitinib, pazopanib, AG-013736, nelfinavir) or PET activity (PTK787/ZK222584), and increased expression of HIF-1alpha (bevacizumab). Moreover, 9 studies reported no change in tumor oxygenation as measured with hypoxic markers (endostatin and SU5416), direct oxygen measurements (anti-VEGF antibody, DC101, arginine deiminase), or radiation response (DC101). Finally, two studies actually reported both increases and decreases when using direct oxygen measurements depending on the time after treatment with bevacizumab or DC101.
Conclusions: While there is clear evidence that tumor oxygenation can improve following AI treatment, consistent with vascular normalization occurring, this is clearly not a universal finding. Importantly the effects on tumor hypoxia/oxygenation status show no relationship to either the specific AI or the assay used to monitor these parameters. These findings suggest that for the combination of AIs with conventional anti-cancer therapies to be most effective it will be important to establish the impact the AI has on the tumor vasculature and associated tumor pathophysiology in a given treatment setting.
Citation Format: Michael R. Horsman, Dietmar W. Siemann. Is the lack of clinical success with antiangiogenic therapy due to vascular normalization not being a universal phenomenon? [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A04.