Anti-angiogenesis as anticancer therapy
Inhibition of tumor angiogenesis suppresses tumor growth in many experimental models. In 2004 an antibody (Avastin®) directed against vascular endothelial growth factor (VEGF) was reported to provide a survival benefit to patients with advanced colorectal cancer, in combination with chemotherapy, and was approved as the first anti-angiogenic drug for use in human cancer therapy. This result validates the concept that inhibition of tumor angiogenesis suppresses tumor growth. Additional antiangiogenic drugs were approved thereafter. Attempts are under way to target lymphatic vessels to inhibit lymphgangiogenesis for therapeutic purposes.
Quantification of tumor angiogenesis and measuring antiangiogenic drugs activities in patients remain unresolved issues. Many approaches have been tested in experimental models and clinical studies, but to date none has been validated for routine use in patients. It is not clear which biomarker best represents angiogenesis and, as a matter of fact, whether there is one at all. The intrinsic complexity of tumor angiogenesis, its multiple regulatory mechanisms and adaptation during therapy, suggest in fact hat different biomarkers will be necessary to give a comprehensive representation of angiogenesis and its therapeutic modulation, depending on the tumor of interest, its stage, the tested drug, the question asked and the clinical stage of development (phase I/II/III). One can distinguish three kinds of biomarkers:
I) Molecular biomarkers. They consist of individual molecules such as growth factors (eg VEGF, FGF), cell surface receptors (eg VEGF-R2, integrins), downstream signaling molecules (eg ERK, AKT) and their modifications (eg activation, phosphorylation), or transcripts for single or multiple genes (eg signatures) and their modifications. Molecular biomarkers are indicative of the molecular events associated with angiogenesis or drug activity.
II) Biological biomarkers. In order to obtain initial information on the effects of these molecular events and their modification on endothelial cell biology, it will be necessary to monitor basic characteristics of endothelial cell functions, such as cell proliferation or death. Blood circulating angiogenesis-associated cells (eg CEC, CECP) may reflect these changes and serve as easily accessible surrogate markers of biological effects. Molecular and cellular biomarkers are important in phase I/II studies, where demonstration of target modification and drug activity is the main goal.
III) Functional biomarkers. Tumor perfusion is the ultimate function of angiogenic vessels, and its modification is likely to reflect significant changes in their physical or functional state. However, acquisition and meaningful interpretation of perfusion and permeability data may be challenging, since changes may be only transient, occur late after drug administration, or not necessarily be representative of all drug effects (eg some TKI concomitantly target tumor and stromal cells). Measurement of perfusion-related parameters (rBV, MTT, rBF, Ktrans) by imaging technique is probably more useful at late phases of development (III) when evidence of activity is already available. Also, imaging techniques can be used to monitor the effects on tumor biology (tumor regression, metabolism).
Clinical endpoints (OS, PFS) will be eventually used to validate the impact of the tested drug on disease progression and patient survival.
Data generated by different classes of biomarkers can be compared to extract valuable information on their relative value and suitability for monitoring, but also to dissect mechanisms of action of the tested drug.