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Understanding tumor progression

Important differences among antitumor strategies

In light of the proposed ongoing effects of VEGF inhibition, it is important to consider the possible reasons for tumor progression, which may vary widely among different antitumor strategies. With agents that target the tumor directly, progression often occurs through mutational pathways, in which tumor cells that are less sensitive to therapy emerge and repopulate the tumor. As a result, the effectiveness of many tumor-targeting agents may diminish over time.^1,24

Agents that target the tumor directly: Progression through mutational pathways¹

1. Tumor cells emerge that are less sensitive to the therapy
2. These less sensitive cells repopulate the tumor, facilitating tumor progression

With agents that target VEGF directly, tumor progression may develop through nonmutational pathways. While the VEGF ligand is a genetically stable protein that is continually expressed throughout tumor development, secondary angiogenic pathways may become activated over time, contributing to further tumor development. Activation of these redundant pathways may occur as a compensatory response to treatment or as a result of tumor cell mutations (ie, mutations that are not associated with direct VEGF inhibition).^24-28 Because VEGF remains the predominant mediator of angiogenesis, one option to consider as tumors progress is to maintain direct VEGF inhibition and supplement it by selectively targeting other emergent pathways.^24,28

Agents that target VEGF directly: Progression through nonmutational pathways^11,28

1. VEGF is continually expressed throughout tumor development
2. As the tumor matures, secondary pathways are activated that contribute to tumor progression

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