Table 4.
Potential Biomarkers of Antiangiogenic Therapy Measured in Blood Circulation in Patients With Glioblastoma
| Plasma Biomarkers | Agent and Regimen | Effect on Biomarker | Comments |
|---|---|---|---|
| VEGF | Bevacizumab with chemoradiation (phase III study) | Not available | Baseline VEGF does not correlate with survival outcomes90 Unclear when the optimal time is for evaluation as pharmacodynamic biomarker after anti-VEGF treatment |
| VEGF | Cediranib alone and with chemotherapy in patients with rGBM (phase II and III studies) Cediranib with chemoradiation in patients with nGBM (phase II study) |
Increase in plasma VEGF | Seen only in cediranib-containing arms in phase III study16 Does not correlate with survival outcomes14,16,69 |
| VEGF | Vandetanib in patients with nGBM (phase II study) | Increase in plasma VEGF | Minor increases at some but not all time-points (weak VEGFR inhibition?)89 |
| VEGF | Vatalanib with chemoradiation in patients with nGBM (phase I study) | Increase in plasma VEGF | Agent has short half-life (weak VEGFR inhibition?)73 |
| VEGF | Aflibercept alone in patients with rGBM (phase II study) | Decrease in free plasma VEGF | Potential accumulation of bound VEGF in blood circulation91 |
| VEGF | Cabozantinib alone in patients with rGBM (phase II study) | Increase in plasma VEGF | Mature data not available93 |
| PlGF | Cediranib alone in patients with rGBM (phase II study) Cediranib with chemoradiation in patients with nGBM (phase II) |
Increase in plasma PlGF | Substantial increases (by 30% to 386% from 8 hours to 112 days) but unclear when the optimal time is for evaluation as pharmacodynamic biomarker after anti-VEGF treatment Does not correlate with survival outcomes16,69 Correlates with perfusion changes measured by MRI16 |
| PlGF | Vandetanib with chemoradiation in patients with nGBM (phase II study) | Increase in plasma PlGF | PlGF initially decreases (at 4 hours) but then increases (by 6% to 40% from day 1 to 22; weak VEGFR inhibition?)89 |
| PlGF | Vatalanib with chemoradiation in patients with nGBM (phase I study) | Increase in plasma PlGF | Sustained but minor increases (by 54% to 61% from 8 hours to 70 days). Agent has short half-life (weak VEGFR inhibition?)73 |
| PlGF | Aflibercept alone in rGBM patients (phase II study) | Increase in plasma PlGF | Dramatic increase in PlGF91; potential accumulation of bound PlGF in blood circulation? Inverse correlation with response91 |
| PlGF | Cabozantinib alone increases plasma PlGF (phase II study) | Increase in plasma PlGF | Mature data not available93 |
| sVEGFR-1 | Cediranib alone in patients with rGBM (phase II study) Cediranib with chemoradiation in patients with nGBM (phase II) |
No change in plasma sVEGFR-1 Decrease in plasma sVEGFR-1 |
An increase in sVEGFR-1 on treatment correlates with survival outcomes in nGBM and rGBM patients16,69 Correlates with perfusion changes measured by MRI69 Unclear whether sVEGFR-1 is a pharmacodynamic or predictive biomarker for anti-VEGF therapy16 |
| sVEGFR-1 | Vandetanib with chemoradiation in patients with nGBM (phase II study) | No change in plasma sVEGFR-1 | High sVEGFR-1 at baseline correlated with survival outcomes in nGBM patients89 |
| sVEGFR-1 | Vatalanib with chemoradiation in patients with nGBM (phase I study) | Increase in plasma sVEGFR-1 | No significant correlation with survival73 |
| sVEGFR-2 | Bevacizumab with chemoradiation (phase III study) | Not available | Baseline sVEGFR-2 does not correlate with survival outcomes90 Bevacizumab may not decrease the plasma VEGFR-2 levels94 |
| sVEGFR-2 | Cediranib alone and with chemotherapy in patients with rGBM (phase II and III studies) | Decrease in plasma sVEGFR-2 | Seen only in cediranib-containing arms in phase III study14 Unclear when the optimal time of evaluation is as pharmacodynamic biomarker after anti-VEGF treatment with TKIs Does not correlate with survival outcomes14,16,69 Correlates with perfusion changes measured by MRI16 |
| sVEGFR-2 | Vandetanib with chemoradiation in patients with nGBM (phase II study) | Decrease in plasma sVEGFR-2 | Change inversely correlated with overall survival89 |
| sVEGFR-2 | Vatalanib with chemoradiation in patients with nGBM (phase I study) | Decrease in plasma sVEGFR-2 | Does not correlate with survival outcomes73 |
| sVEGFR-2 | Cabozantinib alone in patients with rGBM (phase II study) | Decrease in plasma sVEGFR-2 | Mature data not available93 |
| Collagen IV | Cediranib alone in patients with rGBM (phase II study) | Decrease in plasma collagen IV | Early change (at day 1) inversely correlates with PFS92 |
| Collagen IV | Vandetanib with chemoradiation in patients with nGBM (phase II study) | No change in plasma collagen IV | Early change (at day 1) inversely correlates with response (RECIST)89 |
| Collagen IV | Vatalanib with chemoradiation in patients with nGBM (phase I study) | Decrease in plasma collagen IV | Early change (at day 1) inversely correlates with PFS73 |
| bFGF | Cediranib alone or with chemotherapy in patients with nGBM (phase III study) Cediranib with chemoradiation in patients with nGBM (phase II study) |
No consistent change in plasma bFGF Decrease in plasma bFGF |
Does not correlate with survival outcomes16,69 |
| bFGF | Vandetanib with chemoradiation in patients with nGBM (phase II study) | No change in plasma bFGF | Does not correlate with survival outcomes; baseline plasma bFGF inversely associated with increase responses (by RECIST)89 |
| bFGF | Vatalanib with chemoradiation in patients with nGBM (phase I study) | No change in plasma bFGF | Does not correlate with survival outcomes73 |
| Ang-2 | Cediranib alone in patients with rGBM (phase II study) Cediranib with chemoradiation in patients with nGBM (phase II study) |
Decrease in plasma Ang-2 Decrease in plasma Ang-2 |
Decrease is transient in patients with nGBM after cediranib alone69 but more sustained in nGBM after cediranib with chemoradiation16 Does not correlate with survival outcomes16,69 |
| sTie-2 | Cediranib alone in patients with rGBM (phase II study) | Decrease in plasma sTie-2 | Low levels associated with radiographic response; high levels associated with progression69 |
| sTie-2 | Cediranib with chemoradiation in patients with nGBM (phase II study) | No change in plasma sTie-2 | |
| sTie-2 | Vandetanib with chemoradiation in patients with nGBM (phase II study) | Increase in plasma sTie-2 | |
| sTie-2 | Vatalanib with chemoradiation in patients with nGBM (phase I study) | Transient decrease in plasma sTie-2 | Does not correlate with survival outcomes89 |
| CA-9 | Cediranib with chemoradiation in patients with nGBM (phase II study) | Increase in plasma CA-9 | |
| CA-9 | Aflibercept alone in patients with rGBM (phase II study) | Not reported | Plasma CA-9 correlated with plasma VEGF at baseline91 |
| CA-9 | Vandetanib with chemoradiation in patients with nGBM (phase II study) | No change in plasma CA-9 | A rapid decrease in CA-9 (at 4 hours) associated with response (RECIST)89 |
| MMP-9 | Cediranib alone in patients with rGBM (phase II study) | No change in plasma MMP-9 | No association with outcome69 |
| MMP-9 | Aflibercept alone in patients with rGBM (phase II study) | Not reported | An increase at day 28 associated with disease progression91 |
| MMP-2 | Cediranib alone in patients with rGBM (phase II study) | Transient decrease in plasma MMP-2 | An increase in plasma MMP-2 at 8 hours after first administration of cediranib correlated with reduced PFS and OS69 |
| MMP-10 | Cediranib alone in patients with rGBM (phase II study) | Transient decrease and then sustained increase in plasma MMP-10 | No association with outcome69 |
| SDF-1α | Cediranib alone in patients with rGBM (phase II study) Cediranib with chemoradiation in patients with nGBM (phase II study) |
Increase in plasma SDF-1α Increase in plasma SDF-1α |
No association with survival outcomes16,69 Increased levels of SDF-1α associated with radiographic progression69 |
| SDF-1α | Vandetanib with chemoradiation in patients with nGBM (phase II study) | Transient decrease followed by increase in plasma SDF-1α | A subtle drop at 4 hours and a small increase at day 2289 No association with survival outcomes89 |
| SDF-1α | Vatalanib with chemoradiation in patients with nGBM (phase I study) | No change in plasma SDF-1α | |
| IL-8 | Cediranib alone in patients with rGBM (phase II study) Cediranib with chemoradiation in patients with nGBM (phase II study) |
No change in plasma IL-8 Transient increase in plasma IL-8 |
High levels associated with radiographic response after cediranib alone69 Late increase in IL-8 (at day 43) after cediranib and chemoradiation correlated with poor PFS and showed a nonsignificant trend for association with poor OS16 |
| IL-8 | Vatalanib with chemoradiation in patients with nGBM (phase I study) | No change in plasma IL-8 | No association with survival outcomes73 |
| MCP3/CCL7 | Aflibercept in patients with rGBM (phase II study) | Not reported | High baseline levels of CCL7 were associated with improved response91 |
| MIF | Aflibercept in patients with rGBM (phase II study) | Transient decrease in plasma MIF | High baseline levels of MIF were associated with improved response91 |
| CTACK/CCL27 | Aflibercept in patients with rGBM (phase II study) | Not reported | High baseline levels of CCL27 were associated with improved response91 |
| IP-10/CXCL10 | Aflibercept in patients with rGBM (phase II study) | Not reported | High baseline levels of CXCL10 were associated with improved response91 |
Abbreviations: Ang-2, angiopoietin 2; bFGF, basic fibroblast growth factor; CA-9, carbonic anhydrase 9; IL-8, interleukin-8; MMP-2, matrix metalloproteinase 2; MRI, magnetic resonance imaging; nGBM, newly diagnosed glioblastoma; OS, overall survival; PFS, progression-free survival; PlGF, placental-derived growth factor; rGBM, recurrent glioblastoma; SDF-1α, stromal-derived factor 1 alpha; sVEGFR-1, soluble vascular endothelial growth factor receptor 1; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.