ABSTRACT
Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Biomarkers, Tumor/blood , Colorectal Neoplasms/blood , Colorectal Neoplasms/secondary , Receptor, TIE-2/blood , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adult , Aged , Angiopoietin-2/metabolism , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Colorectal Neoplasms/blood supply , Colorectal Neoplasms/drug therapy , Disease Progression , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Models, Biological , Neovascularization, Pathologic/blood , Prognosis , Vascular Endothelial Growth Factor A/metabolismABSTRACT
PURPOSE: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. EXPERIMENTAL DESIGN: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. RESULTS: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P Subject(s)
Angiogenesis Inhibitors/therapeutic use
, Antibodies, Monoclonal/therapeutic use
, Colorectal Neoplasms/blood supply
, Colorectal Neoplasms/drug therapy
, Diagnostic Imaging
, Vascular Endothelial Growth Factor A/immunology
, Adolescent
, Animals
, Antibodies, Monoclonal/pharmacology
, Antibodies, Monoclonal, Humanized
, Bevacizumab
, Cell Line, Tumor
, Drug Delivery Systems
, Female
, Humans
, Mice
, Mice, Nude
, Neovascularization, Pathologic/drug therapy
, Xenograft Model Antitumor Assays
