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Why is continued VEGF inhibition important?

Regrowth of tumor vasculature may occur when VEGF inhibition is stopped

While continued VEGF inhibition is thought to maintain important anti-angiogenic effects that keep tumor cells from growing and spreading, cessation of VEGF suppression may diminish those effects. In preclinical models, withdrawal of an anti-VEGF agent has been shown to result in regrowth of tumor vasculature (Fig. 1).^1-5

While the cessation of VEGF inhibition with anti-VEGF antibodies has been shown to result in eventual regrowth of tumor vessels, it has not been shown to result in a rebound effect (ie, more aggressive/accelerated growth following discontinuation). In one series of preclinical experiments, the tumor recovery rate was found to be slower in tumors following cessation of VEGF inhibition than in control tumors in 25 of 26 (96%) of tumor cell lines studied. This lack of tumor rebound was observed whether VEGF inhibition was applied alone or in combination with chemotherapy.⁶

Fig. 1. Tumor vessel regrowth following withdrawal of an anti-VEGF agent²

Adapted from Vosseler et al 2005. Reproduced with permission from the American Association for Cancer Research.

The rationale for continuing VEGF inhibition

Research suggests that continuing direct VEGF inhibition alone may help preserve antitumor effects achieved following initial combination with chemotherapy. In preclinical models, continuation of VEGF inhibition following initial combination with chemotherapy inhibited tumor recurrence and significantly prolonged survival in mice (Fig. 2).^6,7

Fig. 2. PRECLINICAL EVIDENCE: prolonged survival with continued VEGF inhibition (mouse model)⁶

In vivo experiment using the pancreatic cancer cell line, Bx-PC3.

References:

1.

Mancuso MR, Davis R, Norberg SM, et al. J Clin Invest. 2006;116:2610-2621.

2.

Vosseler S, Mirancea N, Bohlen P, et al. Cancer Res. 2005;65:1294-1305.

3.

Baluk P, Hashizume H, McDonald DM. Curr Opin Genet Dev. 2005;15:102-111.

4.

Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.

5.

Aita M, Fasola G, Defferrari C, et al. Crit Rev Oncol Hematol. 2008;68:183-196.

6.

Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix].

7.

Mabuchi S, Terai Y, Morishige K, et al. Clin Cancer Res. 2008;14:7781-7789.