Biomarkers of response and resistance to antiangiogenic therapy

Abstract

No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I-III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured K(trans), circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1alpha, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.

Figure 1

Candidate biomarkers of response and resistance to antiangiogenic therapy. At baseline, the genotype of VEGF and/or IL-8 might associate with outcome of bevacizumab with chemotherapy. Randomized trials will establish if the biomarkers are predictive or prognostic. Among dynamic biomarkers, the extent of hypertension, decrease in K^trans (in patients with glioblastoma or hepatocellular carcinoma), increase in small (cerebral) blood vessel volume (glioblastoma) and/or increase in circulating collagen IV (glioblastoma) might be predictive of outcome of antiangiogenic therapy. Finally, molecular pathways such as SDF1α (in glioblastoma, hepatocellular carcinoma or renal-cell carcinoma), IL-6 (in hepatocellular carcinoma or renal-cell carcinoma) or bFGF (glioblastoma), and CPCs (in hepatocellular carcinoma) might be associated with resistance to antiangiogenic therapy. Abbreviations: bFGF, basic fibroblast growth factor, CBV, cerebral blood volume; CPC, circulating progenitor cell; IL, interleukin; LDH, lactate dehydrogenase; SDF1α, stromal-cell-derived factor 1α; sICAM1, soluble intracellular adhesion molecule 1.

Figure 2

Modes of vessel recruitment to tumors that might be involved in tumor escape from antiangiogenic therapy. Abbreviations: bFGF, basic fibroblast growth factor; BMC, bone marrow cell; IL-6, interleukin 6; SDF1α, stromal-cell-derived factor 1α. Adapted with permission from Nature Publishing Group © Carmeliet, P. and Jain, R. K. Nature 407, 249–257 (2000).