Abstract 3439: An alternative VEGF-targeted therapy and possible prediction against hepatocellular carcinoma (HCC) using combination of clinically available agents
Authors: Yoshiji Hitoshi , Ikenaka Yasuhide , Noguchi Ryuichi , Kaji Kosuke , Shirai Yusaku , Fukui Hiroshi 
Published: February 2011

The incidence of hepatocellular carcinoma (HCC) is increasing not only in Asia but also in Europe and United States. Since the high-risk group of either primary or secondary HCC development seems to be clearer than in the other types of tumors, it is likely that chemopreventive agents will be beneficial in improving the prognosis of HCC. No chemopreventive agent, however, has been approved against HCC yet. Since neovascularization plays a pivotal role in HCC, an angiostatic agent is considered as one of the promising approaches. Although the multi-kinase inhibitor, sorafenib, has recently been approved for advanced HCC in many countries, there seem to be several serious concerns to employ this agent for chemoprevention against HCC. As long-term administration is required and the drug metabolism is usually hypoactive in patients with cirrhosis, a safety-proved agent would be preferable for chemoprevention against HCC. Most patients show adverse reactions with sorafenib, and several symptoms are very severe. The aim of this study was to develop a vascular endothelial growth factor (VEGF)-targeted new anti-angiogenic therapy against HCC using combination of clinically available safe agents. Moreover, since it is an imperative issue to find serum predictive biomarkers of clinical benefit, we tried to find a useful marker. We previously reported that the clinically used anti-osteoporosis agent; vitamin K (VK), and the anti-hypertensive agent; angiotensin-converting enzyme inhibitor (ACE-I), exerted potent anti-angiogenic activities along with suppression of VEGF at clinically comparable low doses in a basic study. In the clinical practice, the combination treatment of VK (menatetrenone; 45 mg/day) and ACE-I (perindopril; 4 mg/day) markedly inhibited the cumulative recurrence of HCC along with suppression of VEGF for 54 months after curative therapy. The serum level of alpha fetoprotein-L3 (AFP-L3), which indicates the presence of latent HCC, was also suppressed almost in parallel with VEGF. Chronological studies reveled that the VEGF and AFP-L3 were significantly decreased in patients without recurrence at 6 and 12 months after the treatment, respectively. We also examined the alteration of soluble form of VEGF receptor-2 (sVEGFR-2), and found that a significant suppression of sVEGFR-2 level could be achieved within three months after the treatment. Collectively, the alteration of the serum level of VEGF-related proteins, especially VEGFR-2, could be used as a biomarker for the therapeutic efficacy. These results indicate that this combination treatment may represent a potential new strategy for secondary chemoprevention of HCC with effective prediction of the clinical outcome since both agents are widely used in the clinical practice without serious side effects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3439.