Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Murukesh, Nishanth; Dive, Caroline; Jayson, Gordon C

doi:10.1038/sj.bjc.6605483

Cited by 214 publications

(163 citation statements)

References 98 publications

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“…Consistent with prior reports by our group and others evaluating anti-VEGF monotherapy, in this study MMP-2, PlGF, VCAM-1, and VEGF-D were increased, while Ang-2, MMP-9, and s-VEGFR2 were decreased in response to the combination of bevacizumab and everolimus. The magnitudes of these changes appear to be broadly consistent with those previously described for bevacizumab monotherapy (18,22), suggesting these changes were driven primarily by VEGF but not mTOR inhibition.…”

Section: Discussionsupporting

confidence: 73%

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

Liu

Starr

Brady

et al. 2015

Molecular Cancer Therapeutics

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A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-a, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFb-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P ¼ 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-a, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFb-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology.

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Section: Discussionsupporting

confidence: 73%

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

Liu

Starr

Brady

et al. 2015

Molecular Cancer Therapeutics

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“…Conversely, oral VEGFR-2 inhibitors reduce circulating levels of the receptor, accompanied by increased VEGF production (49, 50, reviewed in ref. 51) as a compensatory response.…”

Section: Discussionmentioning

confidence: 99%

Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004

Atzori

Strauss

Geese

et al. 2013

Clinical Cancer Research

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Purpose: Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis.Experimental Design: Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m 2 twice daily (DL1 and DL2) or 1,000 mg/m 2 twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis.Results: Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m 2 twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed. Conclusions: Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m 2 twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.

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“…Similar to sVEGFR-1, sVEGFR-2 is unable to carry out tyrosine transphosphorylation and activate the downstream signal transduction of angiogenesis, due to the lack of the tyrosine kinase domain (20). The activation of VEGFR-2 reportedly plays a significant role in tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…A study recently showed that hepatocyte growth factor (HGF) may be a surrogate marker for the clinical benefit of sorafenib (20). In addition to HGF, various molecules have been considered as useful biological markers for anti-angiogenic therapy, such as circulating endothelial progenitor cells and the soluble form of VEGF receptors (20).…”

Section: Introductionmentioning

confidence: 99%

Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

et al. 2010

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Abstract. The identification of biomarkers of anti-angiogenic therapy that predict clinical benefit is of vital importance. We previously reported that a combination treatment with clinically available safe agents, specifically angiotensin-converting enzyme inhibitor (ACE-I) and vitamin K (VK), inhibited the cumulative recurrence of hepatocellular carcinoma (HCC) via suppression of the vascular endothelial growth factor (VEGF). The present study aimed to identify non-invasive biological markers that predict the clinically beneficial effect of this combination regimen. A combination of ACE-I (perindopril; 4 mg/day) and VK (menatetrenone; 45 mg/day) was administered for 54 months following curative therapy for HCC. The cumulative recurrence and several indices, which are reportedly considered as biological markers of anti-angiogenic therapies, were analyzed. The combined treatment of ACE-I and VK markedly inhibited the cumulative recurrence of HCC during the 54-month follow-up. The serum VEGF and soluble VEGF receptor (sVEGFR)-2 were significantly suppressed with this combination regimen, whereas sVEGFR-1 was not. In HCC patients without recurrence, a significant suppression of VEGF and sVEGFR-2 was achieved within 6 and 3 months after treatment, respectively. In conclusion, the combination treatment of ACE-I and VK is a potentially novel anti-angiogenic strategy for secondary chemoprevention against HCC since the two agents are widely used in clinical practice without serious side effects. Furthermore, sVEGFR-2 may become a useful clinical predictive marker of this combination treatment.

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Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Cited by 214 publications

References 98 publications

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

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

Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004

Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

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