Modulation of circulating protein biomarkers following TRC105 (anti‐endoglin antibody) treatment in patients with advanced cancer

Abstract

TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin-2 [Ang-2], insulin-like growth factor-binding protein-3 [IGFBP-3], plasminogen activator inhibitor-1 [PAI-1] total, platelet-derived growth factor [PDGF]-AA, PDGF-BB, thrombospondin-1 [TSP-1], and vascular endothelial growth factor [VEGF]-D). Meanwhile, seven markers were upregulated by C2D1 (E-Cadherin, soluble Endoglin [sEnd], E-Selectin, interleukin-6 [IL-6], osteopontin [OPN], TSP-2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang-2, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), IGFBP-1, IL-6, TSP-2, and vascular cell adhesion molecule-1 (VCAM-1). A statistical trend was also seen for increases of VEGF-A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma-based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang-2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105's anti-angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF-targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.

Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus

“…Other candidate clinical predictors for bevacizumab have also been described, including VEGF ligands, HGF, and other inflammatory mediators (28). We and others have also described reproducible patterns of change in multiple markers with anti-VEGF therapy, as well as with other antiangiogenic therapies (17)(18)(19)(20)(29)(30)(31).…”

“…This approach has the potential to identify markers that may predict for greater or lesser benefit from anti-VEGF therapies, other antiangiogenic agents, and combination regimens. Previously, these candidate markers were tested in other clinical settings and specific markers have been identified to have potential prognostic and/or predictive value (17)(18)(19)(20).…”

Inhibition of Endoglin–GIPC Interaction Inhibits Pancreatic Cancer Cell Growth

“…Currently, anti-endoglin therapy is being explored as a therapeutic in several cancers as an anti-angiogenic agent (16–19). The present study shows that endoglin-targeted therapies in pancreatic cancer may offer an additional advantage by targeting not only the vasculature but also the tumor cells expressing endoglin.…”

“…The specific expression pattern of endoglin in tumoral vessels indicates that it may be a worthy target molecule for anti-angiogenic therapy in cancer. In deed, anti-endoglin therapy is currently being explored as an anti-angiogenic therapeutic in several cancers (16–19). …”

Interactions between osteopontin and vascular endothelial growth factor: Implications for cancer

“…It is over-expressed on rapidly proliferating cancer cells. An antibody against endoglin increases the levels of OPN and VEGF-A, while decreasing VEGF-D levels over pre-treatment baseline levels [152].…”