Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition

Abstract

Inhibition of hypoxia inducible factor-1 (HIF-1) is an attractive therapeutic strategy to target the tumor microenvironment. However, HIF-1 inhibitors may have limited activity as single agents and combination therapies may be required. We tested the hypothesis that HIF-1 inhibition in a hypoxic-stressed tumor microenvironment, which could be generated by administration of antiangiogenic agents, may result in a more pronounced therapeutic effect. The activity of bevacizumab, either alone or in combination with the HIF-1α inhibitor topotecan, was evaluated in U251-HRE xenografts. Tumor tissue was collected at the end of treatment and changes in tumor oxygenation, angiogenesis, proliferation, apoptosis, HIF-1α levels, HIF-1 target genes, and DNA damage were evaluated. Bevacizumab decreased microvessel-density and increased intratumor-hypoxia, but did not induce apoptosis. Moreover, bevacizumab alone caused a significant increase of HIF-1-dependent gene expression in tumor tissue. Addition of a low dose of daily topotecan to bevacizumab significantly inhibited tumor growth, relative to mice treated with topotecan or bevacizumab alone (P < 0.01). The addition of topotecan to bevacizumab was also associated with profound inhibition of HIF-1 transcriptional activity, significant inhibition of proliferation, and induction of apoptosis. Importantly, DNA damage induced by topotecan alone was not augmented by addition of bevacizumab, suggesting that increased cytotoxic activity did not account for the increased antitumor effects observed. These results strongly suggest that combination of anti-vascular endothelial growth factor antibodies with HIF-1 inhibitors is an attractive therapeutic strategy targeting in the hypoxic tumor microenvironment.

Chemotherapy Counteracts Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice

“…We investigated the effect on metastasis formation of sunitinib with topotecan administered daily at suboptimal doses, previously reported to affect the hypoxic tumor microenvironment (34,35).…”

Non-invasive monitoring of hypoxia-inducible factor activation by optical imaging during antiangiogenic treatment in a xenograft model of ovarian carcinoma

“…Unexpectedly, we detected a gradual decrease in HIF reporter activity over the duration of bevacizumab treatment. In the few publications that evaluated the effect of bevacizumab using a luminescent HIF reporter results were divergent: activation of the reporter in a lung adenocarcinoma model (15) and inhibition of the reporter in a glioblastoma model (16). A decrease in HIF reporter activity by antiangiogenic treatment could be explained by: i) a decrease in intratumoral hypoxia caused by vascular normalization; ii) an increase in intratumoral hypoxia that may cause a decrease in luciferase activity due to limited oxygen availability; iii) reduced availability of luciferase substrate as a consequence of reduced vascularization; and iv) an increase in intratumoral hypoxia compensated with a decrease in the number of viable cells.…”

“…We used the 9xHRE-luciferase (9xHRE-luc) reporter vector that harbors nine copies of the HRE derived from the VEGFA gene upstream of a minimal rat prolactin promoter driving the expression of the firefly luciferase gene (12). Similar vectors, containing a variable number of HREs and diverse reporter genes (luciferase or EGFP) have been developed and used as functional reporters for optical imaging over the last 5 years (13)(14)(15)(16)(17)(18)(19). Hypoxic conditions lead to hypoxia inducible factor (HIF) stabilization and subsequent induction of luciferase reporter gene expression through binding of HIF to HREs in the reporter and activation of transcription driven by HIF.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…This strategy provided superior anti-angiogenic effects, which also resulted in superior anti-tumour activity in a glioblastoma xenograft model. 3,121 Another remarkable preclinical study was performed by Kerbel and colleagues at the University of Toronto. They demonstrated that combining pazopanib (Votrient s ; GlaxoSmithKline), a VEGF receptor inhibitor, with metronomic TPT, is synergistic and resulted in 100% survival of the drug combination (but not the individual monotherapies) after 6 months of continuous therapy in an aggressive, metastatic, orthotropic xenograft ovarian model.…”