Tumor blood vessels are markedly abnormal due to the excess production by tumor cells of inflammatory and angiogenic factors such as vascular endothelial growth factor (VEGF). Vascular normalization employing VEGF pathway inhibitors has become standard of care for some cancers especially in combination with other standard cancer therapies.
Normalization of the tumor vasculature reduces tumor progression possibly by “pruning” and reducing the growth of tumor vessels decreasing local tumor growth, by decreasing escape of tumor cells resulting in less metastatic spread, by improving the anti-tumor immune response, or by enhancing the antitumor effects of standard cancer therapeutics including chemotherapy, radiation therapy and immunotherapy.
Although VEGF pathway inhibitors have proven effective in various tumor types, the vascular normalizing effects and concomitantly, the antitumor effects are often modest and/or short lived. The limited efficacy of VEGF pathway inhibitors may be secondary to production of other inflammatory/angiogenic factors possibly triggered by VEGF pathway inhibition. In addition, VEGF pathway inhibitors can also have adverse cardiovascular effects such as hypertension, thrombosis and kidney injury due to adverse effects of inhibiting normal VEGF signaling in nontumor vessels. Based on the promise and limitations of VEGF pathway inhibitors, alternative or complementary pathways to tumor vascular normalization have been the subject of intensive research.
Relevant to Aerpio’s Tie2 activators, preclinical studies have shown that restoring Tie2 pathway activation with either genetic or pharmacologic interventions, normalizes the tumor vasculature in association with reduced tumor progression. Moreover, recent studies indicate that combining Tie2 activation with VEGF pathway inhibition, may be more effective than either approach alone. Consistent with these findings, razuprotafib (AKB-9778) Aerpio’s lead Tie2 activator has shown vascular normalizing effects in mouse models of breast and colon cancer along with enhanced tumor activity in combination with chemotherapy, radiation therapy and high dose IL-2 immunotherapy. Based on these data, Aerpio is developing a novel bispecific Tie2 activator/VEGF pathway inhibitor as a potentially superior approach to tumor vascular normalization.