Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

Abstract

The identification of biomarkers of anti-angiogenic therapy that predict clinical benefit is of vital importance. We previously reported that a combination treatment with clinically available safe agents, specifically angiotensin-converting enzyme inhibitor (ACE-I) and vitamin K (VK), inhibited the cumulative recurrence of hepatocellular carcinoma (HCC) via suppression of the vascular endothelial growth factor (VEGF). The present study aimed to identify non-invasive biological markers that predict the clinically beneficial effect of this combination regimen. A combination of ACE-I (perindopril; 4 mg/day) and VK (menatetrenone; 45 mg/day) was administered for 54 months following curative therapy for HCC. The cumulative recurrence and several indices, which are reportedly considered as biological markers of anti-angiogenic therapies, were analyzed. The combined treatment of ACE-I and VK markedly inhibited the cumulative recurrence of HCC during the 54-month follow-up. The serum VEGF and soluble VEGF receptor (sVEGFR)-2 were significantly suppressed with this combination regimen, whereas sVEGFR-1 was not. In HCC patients without recurrence, a significant suppression of VEGF and sVEGFR-2 was achieved within 6 and 3 months after treatment, respectively. In conclusion, the combination treatment of ACE-I and VK is a potentially novel anti-angiogenic strategy for secondary chemoprevention against HCC since the two agents are widely used in clinical practice without serious side effects. Furthermore, sVEGFR-2 may become a useful clinical predictive marker of this combination treatment.

Figure 1

Cumulative recurrence of secondary HCC after curative therapy with the combination treatment of ACE-I and VK for 54 months. The combination treatment of ACE-I and VK (G2, n=26) significantly inhibited the cumulative recurrence of HCC as compared to the control group (G1, n=28). ^*Statistically significant differences between G1 and G2 (p<0.01).

Figure 2

Effects of the combination treatment of ACE-I and VK on serum VEGF, sVEGFR-1 and sVEGFR-2 levels. (A) The serum VEGF level in the control group (G1) increased after 12 months, whereas the combination treatment of ACE-I and VK (G2) markedly attenuated the VEGF level as compared to the pre-treatment level. (B) No significant differences were noted in sVEGFR-1 between the pre-treatment and post-treatment levels in the two groups. (C) On the other hand, sVEGFR-2 was markedly decreased by the combination treatment of ACE-I and VK, whereas the serum level of sVEGFR2 in the control group increased. The data represent means ± SD (n=15). ^*Statistically significant differences between G1 and G2 (p<0.01).

Figure 3

Chronological alterations of VEGF and sVEGFR-2 during 12 months of treatment in patients in the treated group without HCC recurrence. VEGF expression gradually decreased, and the expression level at 6 months after treatment was statistically significant as compared to the pre-treatment basal level. The decrease in sVEGFR-2 expression occurred earlier than that of VEGF. sVEGFR-2 expression was noted to have already significantly decreased at 3 months after ACE-I and VK combination treatment. The data represent the means ± SD (n=25). ^*Statistically significant differences as compared to the pre-treatment basal level (p<0.01).