Why do tumors progress?
An evolving understanding of tumor biology brings new hypotheses about the mechanisms of tumor progression
In devising effective antitumor strategies over time, it is important to consider the possible reasons for tumor progression, which may vary widely among different modalities. (Table 1).
Tumor cells are typically considered to be genetically unstable. With agents that target tumor cells directly, such as chemotherapy and some TKIs, progression may therefore occur as a result of acquired resistance. Mechanisms of acquired resistance include activation of efflux pumps (which prevents the accumulation of an agent in the cell) and mutations on or inside the cell surface (which reduce the ability of an agent to bind to or inhibit its target). As a result, the effectiveness of many tumor-targeting agents may diminish over time.1-7
Based on preclinical observations, it has been proposed that both endothelial cells and the VEGF ligand are genetically stable. Therefore, escape from agents that directly target the VEGF ligand is generally not thought to occur through acquired resistance but rather through the activation of secondary pathways. For example, while VEGF is present throughout the tumor life cycle, secondary angiogenic factors that function independently of VEGF can become upregulated over time (Fig. 1). This activation of secondary pathways is thought to be innate to tumor biology and not directly related to the targeting of the VEGF ligand.1,8-11
Fig. 1. Emergence of secondary angiogenic factors over the tumor life cycle11-15
Table 1. Current understanding of the mechanisms that drive tumor progression1-10
| Acquired resistance |
Activation of secondary pathways |
|
|---|---|---|
| Involves mutational pathways? | Yes | No |
| Results in loss of binding/inhibitory effects? |
Yes | No |
| Observed with agents that target VEGF extracellularly? |
No | Yes |
While other factors may become activated, the VEGF ligand remains a predominant mediator of angiogenesis. And because it is genetically stable and continually expressed, direct VEGF ligand inhibition remains a rational strategy throughout tumor development. One strategy being evaluated is maintaining direct VEGF ligand inhibition over time while selectively targeting other relevant pathways as they emerge.1,8
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