Skip to main content
Top
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma

Authors: Maurizio Martini, Ivana de Pascalis, Quintino Giorgio D’Alessandris, Vincenzo Fiorentino, Francesco Pierconti, Hany El-Sayed Marei, Lucia Ricci-Vitiani, Roberto Pallini, Luigi Maria Larocca

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Vascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant.

Methods

We assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients’ clinical outcome.

Results

In athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively).

Conclusions

Quantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.
Appendix
Available only for authorised users
Literature
1.
go back to reference Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.CrossRefPubMedPubMedCentral Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.CrossRefPubMedPubMedCentral
2.
go back to reference Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8:610–22.CrossRefPubMed Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8:610–22.CrossRefPubMed
3.
go back to reference Huang WJ, Chen WW, Zhang X. Glioblastoma multiforme: effect of hypoxia and hypoxia inducible factors on therapeutic approaches. Oncol Lett. 2016;12:2283–8.CrossRefPubMedPubMedCentral Huang WJ, Chen WW, Zhang X. Glioblastoma multiforme: effect of hypoxia and hypoxia inducible factors on therapeutic approaches. Oncol Lett. 2016;12:2283–8.CrossRefPubMedPubMedCentral
4.
go back to reference Brat DJ, Castellano Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res. 2004;64:920–7.CrossRefPubMed Brat DJ, Castellano Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res. 2004;64:920–7.CrossRefPubMed
5.
6.
go back to reference Lombardi G, Pambuku A, Bellu L, Farina M, Della Puppa A, Denaro L, et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2017;111:94–102.CrossRefPubMed Lombardi G, Pambuku A, Bellu L, Farina M, Della Puppa A, Denaro L, et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2017;111:94–102.CrossRefPubMed
7.
go back to reference Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–9.CrossRefPubMed Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–9.CrossRefPubMed
8.
go back to reference Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.CrossRefPubMed Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.CrossRefPubMed
9.
go back to reference Friedman HS, Prado MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.CrossRefPubMed Friedman HS, Prado MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.CrossRefPubMed
10.
go back to reference Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.CrossRefPubMed Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.CrossRefPubMed
11.
go back to reference Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.CrossRefPubMedPubMedCentral Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.CrossRefPubMedPubMedCentral
12.
13.
go back to reference Clark AJ, Lamborn KR, Butowski NA, Chang SM, Prados MD, Clarke JL, et al. Neurosurgical management and prognosis of patients with glioblastoma that progresses during bevacizumab treatment. Neurosurgery. 2012;70:361–70.CrossRefPubMed Clark AJ, Lamborn KR, Butowski NA, Chang SM, Prados MD, Clarke JL, et al. Neurosurgical management and prognosis of patients with glioblastoma that progresses during bevacizumab treatment. Neurosurgery. 2012;70:361–70.CrossRefPubMed
15.
go back to reference Lambrechts D, de Haas HJL S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31:1219–30.CrossRefPubMed Lambrechts D, de Haas HJL S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31:1219–30.CrossRefPubMed
16.
go back to reference Finley SD, Popel AS. Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms. AAPS J. 2012;3:500–9.CrossRef Finley SD, Popel AS. Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms. AAPS J. 2012;3:500–9.CrossRef
17.
go back to reference Vempati P, Popel AS, Gabhann FM. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 2014;25:1–19.CrossRefPubMed Vempati P, Popel AS, Gabhann FM. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 2014;25:1–19.CrossRefPubMed
18.
go back to reference Ferrara N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell. 2010;21:687–90.CrossRefPubMedPubMedCentral Ferrara N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell. 2010;21:687–90.CrossRefPubMedPubMedCentral
19.
go back to reference D'Alessandris QG, Martini M, Cenci T, Capo G, Ricci-Vitiani L, Larocca LM, et al. VEGF isoforms as outcome biomarker for anti-angiogenic therapy in recurrent glioblastoma. Neurology. 2015;84:1906–8.CrossRefPubMed D'Alessandris QG, Martini M, Cenci T, Capo G, Ricci-Vitiani L, Larocca LM, et al. VEGF isoforms as outcome biomarker for anti-angiogenic therapy in recurrent glioblastoma. Neurology. 2015;84:1906–8.CrossRefPubMed
20.
go back to reference Finley SD, Engel-Stefanini MO, Imoukhuede PI, Popel AS. Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies. BMC Syst Biol. 2011;5:193.CrossRefPubMedPubMedCentral Finley SD, Engel-Stefanini MO, Imoukhuede PI, Popel AS. Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies. BMC Syst Biol. 2011;5:193.CrossRefPubMedPubMedCentral
21.
go back to reference D'Alessandris QG, Biffoni M, Martini M, Runci D, Buccarelli M, Cenci T, et al. The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response. Neuro-Oncology. 2017;19:1097–108.CrossRefPubMed D'Alessandris QG, Biffoni M, Martini M, Runci D, Buccarelli M, Cenci T, et al. The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response. Neuro-Oncology. 2017;19:1097–108.CrossRefPubMed
22.
go back to reference Guo P, Xu L, Pan S, Brekken RA, Yang ST, Whitaker GB, et al. Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer Res. 2001;61:8569–77.PubMed Guo P, Xu L, Pan S, Brekken RA, Yang ST, Whitaker GB, et al. Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer Res. 2001;61:8569–77.PubMed
23.
go back to reference D'Alessandris QG, Montano N, Cenci T, Martini M, Lauretti L, Bianchi F, et al. Targeted therapy with bevacizumab and erlotinib tailored to the molecular profile of patients with recurrent glioblastoma. Preliminary experience. Acta Neurochir. 2013;155:33–40.CrossRefPubMed D'Alessandris QG, Montano N, Cenci T, Martini M, Lauretti L, Bianchi F, et al. Targeted therapy with bevacizumab and erlotinib tailored to the molecular profile of patients with recurrent glioblastoma. Preliminary experience. Acta Neurochir. 2013;155:33–40.CrossRefPubMed
24.
go back to reference Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, et al. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993;91:153–9.CrossRefPubMedPubMedCentral Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, et al. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993;91:153–9.CrossRefPubMedPubMedCentral
25.
go back to reference Kazemi M, Carrer A, Moimas S, Zandonà L, Bussani R, Casagranda B, et al. VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans. Cancer Gene Ther. 2016;23:125–32.CrossRefPubMed Kazemi M, Carrer A, Moimas S, Zandonà L, Bussani R, Casagranda B, et al. VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans. Cancer Gene Ther. 2016;23:125–32.CrossRefPubMed
26.
27.
go back to reference Finley SD, Popel AS. Effect of tumor microenvironment on tumor VEGF during snti-VEGF treatment: systems biology predictions. J Natl Cancer Inst. 2013;105:802–11.CrossRefPubMedPubMedCentral Finley SD, Popel AS. Effect of tumor microenvironment on tumor VEGF during snti-VEGF treatment: systems biology predictions. J Natl Cancer Inst. 2013;105:802–11.CrossRefPubMedPubMedCentral
28.
go back to reference Iliadis G, Selviaridis P, Kalogera-Fountzila A, Fragkoulidi A, Baltas D, Tselis N, et al. The importance of tumor volume in the prognosis of patients with glioblastoma: comparison of computerized volumetry and geometric models. Strahlenther Onkol. 2009;185:743–50.CrossRefPubMed Iliadis G, Selviaridis P, Kalogera-Fountzila A, Fragkoulidi A, Baltas D, Tselis N, et al. The importance of tumor volume in the prognosis of patients with glioblastoma: comparison of computerized volumetry and geometric models. Strahlenther Onkol. 2009;185:743–50.CrossRefPubMed
Metadata
Title
VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma
Authors
Maurizio Martini
Ivana de Pascalis
Quintino Giorgio D’Alessandris
Vincenzo Fiorentino
Francesco Pierconti
Hany El-Sayed Marei
Lucia Ricci-Vitiani
Roberto Pallini
Luigi Maria Larocca
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4442-2

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine