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Okawa M, Yamakuchi M, Bibek A, Takenouchi K, Maywar DN, Yamada S, Inoue K, Higurashi K, Nakazawa J, Kawahira M, Kodama T, Tanoue K, Oyama Y, Higashi S, Fujisaki C, Hashinokuchi H, Tabaru A, Kanda H, Tachioka S, Imoto Y, Hashiguchi T, Soga Y. Plasma and serum concentrations of VEGF-A121, but not of VEGF-A165, increase post-bevacizumab administration. PLoS One 2024; 19:e0316035. [PMID: 39700124 DOI: 10.1371/journal.pone.0316035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment. METHODS An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165-the major isoforms of VEGF-A-and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy. RESULTS The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of -73.8 pg/mL, 95% CI [-149.4, -10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood. CONCLUSIONS The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care.
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Affiliation(s)
- Masashi Okawa
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Munekazu Yamakuchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Aryal Bibek
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kazunori Takenouchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Drew N Maywar
- Electrical and Computer Engineering Technology, Rochester Institute of Technology, Rochester, New York, United States of America
| | | | | | | | - Junichi Nakazawa
- Department of Medical Oncology, Kagoshima City Hospital, Kagoshima, Japan
| | - Masahiro Kawahira
- Department of Medical Oncology, Kagoshima City Hospital, Kagoshima, Japan
| | - Tomoko Kodama
- Department of Medical Oncology, Kagoshima City Hospital, Kagoshima, Japan
| | - Kiyonori Tanoue
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Yoko Oyama
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Sadayuki Higashi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Chieko Fujisaki
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | | | - Akito Tabaru
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hideaki Kanda
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shuji Tachioka
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yutaka Imoto
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Teruto Hashiguchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Yoshiharu Soga
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Lai V, Neshat SY, Rakoski A, Pitingolo J, Doloff JC. Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity. Adv Drug Deliv Rev 2021; 179:113920. [PMID: 34384826 DOI: 10.1016/j.addr.2021.113920] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/15/2022]
Abstract
Metronomic chemotherapy has been shown to elicit anti-tumor immune response and block tumor angiogenesis distinct from that observed with maximal tolerated dose (MTD) therapy. This review delves into the mechanisms behind anti-tumor immunity and seeks to identify the differential effect of dosing regimens, including daily low-dose and medium-dose intermittent chemotherapy (MEDIC), on both innate and adaptive immune populations involved in observed anti-tumor immune response. Given reports of VEGF/VEGFR blockade antagonizing anti-tumor immunity, drug choice, dose, and selective delivery determined by advanced formulations/vehicles are highlighted as potential sources of innovation for identifying anti-angiogenic modalities that may be combined with metronomic regimens without interrupting key immune players in the anti-tumor response. Engineered drug delivery mechanisms that exhibit extended and local release of anti-angiogenic agents both alone and in combination with chemotherapeutic treatments have also been demonstrated to elicit a potent and potentially systemic anti-tumor immune response, favoring tumor regression and stasis over progression. This review examines this interplay between various cancer models, the host immune response, and select anti-cancer agents depending on drug dosing, scheduling/regimen, and delivery modality.
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Affiliation(s)
- Victoria Lai
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sarah Y Neshat
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Amanda Rakoski
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - James Pitingolo
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Joshua C Doloff
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Materials Science and Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, Division of Cancer Immunology, Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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3
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Marisi G, Scarpi E, Passardi A, Nanni O, Pagan F, Valgiusti M, Casadei Gardini A, Neri LM, Frassineti GL, Amadori D, Ulivi P. IL-8 and thrombospondin-1 as prognostic markers in patients with metastatic colorectal cancer receiving bevacizumab. Cancer Manag Res 2018; 10:5659-5666. [PMID: 30532588 PMCID: PMC6241685 DOI: 10.2147/cmar.s181570] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Purpose Bevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer. Molecular predictors of B efficacy have still not been identified. We analyzed the role of 22 angiogenesis-associated proteins in patient outcome. Patients and methods Serum samples collected at baseline and at the first clinical evaluation were available for 58 patients enrolled in the randomized multicenter ITACa trial and who received CT+ B. Serum protein levels were determined using multiplex ELISA. Results Patients with baseline ≥145 pg/mL IL-8 showed shorter median progression-free survival and overall survival (OS) than those with lower levels (6.5 vs 6. 12.6 months; HR 7.39, P<0.0001 and 8.7 vs 28.8 months, HR 7.68, P<0.001, respectively). Moreover, patients with baseline thrombospondin-1 levels ≥12,000 ng/mL had a better median OS than those with lower levels (34.5 vs 13.1 months, HR 0.43, P=0.007). Patients with a ≥20% reduction in IL-8 levels from baseline to first clinical evaluation showed a better progression-free survival and OS than the others (HR 0.41, P=0.005 and HR 0.43, P=0.007, respectively). Conclusion Baseline IL-8 and thrombospondin-1 levels and reduced IL-8 during B treatment could represent potential prognostic markers in metastatic colorectal cancer.
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Affiliation(s)
- Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy,
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Flavia Pagan
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Luca Maria Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44100, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy,
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Zhao C, Isenberg JS, Popel AS. Human expression patterns: qualitative and quantitative analysis of thrombospondin-1 under physiological and pathological conditions. J Cell Mol Med 2018; 22:2086-2097. [PMID: 29441713 PMCID: PMC5867078 DOI: 10.1111/jcmm.13565] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/07/2018] [Indexed: 12/12/2022] Open
Abstract
Thrombospondin-1 (TSP-1), a matricellular protein and one of the first endogenous anti-angiogenic molecules identified, has long been considered a potent modulator of human diseases. While the therapeutic effect of TSP-1 to suppress cancer was investigated in both research and clinical settings, the mechanisms of how TSP-1 is regulated in cancer remain elusive, and the scientific answers to the question of whether TSP-1 expressions can be utilized as diagnostic or prognostic marker for patients with cancer are largely inconsistent. Moreover, TSP-1 plays crucial functions in angiogenesis, inflammation and tissue remodelling, which are essential biological processes in the progression of many cardiovascular diseases, and therefore, its dysregulated expressions in such conditions may have therapeutic significance. Herein, we critically analysed the literature pertaining to TSP-1 expression in circulating blood and pathological tissues in various types of cancer as well as cardiovascular and inflammation-related diseases in humans. We compare the secretion rates of TSP-1 by different cancer and non-cancer cells and discuss the potential connection between the expression changes of TSP-1 and vascular endothelial growth factor (VEGF) observed in patients with cancer. Moreover, the pattern and emerging significance of TSP-1 profiles in cardiovascular disease, such as peripheral arterial disease, diabetes and other related non-cancer disorders, are highlighted. The analysis of published TSP-1 data presented in this review may have implications for the future exploration of novel TSP-1-based treatment strategies for cancer and cardiovascular-related diseases.
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Affiliation(s)
- Chen Zhao
- Department of Biomedical EngineeringSchool of MedicineJohns Hopkins UniversityBaltimoreMDUSA
| | - Jeffrey S. Isenberg
- Division of Pulmonary, Allergy and Critical CareDepartment of MedicineHeart, Lung, Blood and Vascular Medicine InstituteUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Aleksander S. Popel
- Department of Biomedical EngineeringSchool of MedicineJohns Hopkins UniversityBaltimoreMDUSA
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5
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Alidzanovic L, Starlinger P, Schauer D, Maier T, Feldman A, Buchberger E, Stift J, Koeck U, Pop L, Gruenberger B, Gruenberger T, Brostjan C. The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance. Oncotarget 2018; 7:57197-57212. [PMID: 27527865 PMCID: PMC5302983 DOI: 10.18632/oncotarget.11084] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 07/26/2016] [Indexed: 12/19/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) has become a major target in cancer treatment as it promotes tumor angiogenesis. Therapy with anti-VEGF antibody bevacizumab reportedly induces high levels of circulating VEGF which may potentially contribute to resistance. Based on animal or computational models, mechanisms of VEGF induction by bevacizumab have been proposed but not verified in the clinical setting. Hence, we evaluated sixty patients with colorectal cancer metastases for changes in plasma VEGF during neoadjuvant/conversion and adjuvant chemotherapy with or without bevacizumab. VEGF expression was assessed in tissue sections of liver metastases. The VEGF source was investigated with in vitro cultures of tumor, endothelial cells, fibroblasts and platelets, and potential protein stabilization due to anti-VEGF therapy was addressed. A VEGF rise was observed in blood of bevacizumab patients but not in chemotherapy controls, and VEGF was found to be largely complexed by the antibody. A comparable VEGF increase occurred in the presence (neoadjuvant) and absence of the tumor (adjuvant). Accordingly, VEGF expression in tumor tissue was not determined by bevacizumab treatment. Investigations with isolated cell types did not reveal VEGF production in response to bevacizumab. However, antibody addition to endothelial cultures led to a dose-dependent blockade of VEGF internalization and hence stabilized VEGF in the supernatant. In conclusion, the VEGF rise in cancer patients treated with bevacizumab is not originating from the tumor. The accumulation of primarily host-derived VEGF in circulation can be explained by antibody interference with receptor-mediated endocytosis and protein degradation. Thus, the VEGF increase in response to bevacizumab therapy should not be regarded as a tumor escape mechanism.
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Affiliation(s)
- Lejla Alidzanovic
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Patrick Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Dominic Schauer
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Thomas Maier
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Alexandra Feldman
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Elisabeth Buchberger
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Judith Stift
- Department of Pathology, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Ulrike Koeck
- Department of Neuroimmunology, Medical University of Vienna, Center for Brain Research, 1090 Vienna, Austria
| | - Lorand Pop
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
| | - Birgit Gruenberger
- Department of Internal Medicine, Hospital of The Merciful Brothers, 1020 Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria.,Current address: Department of Surgery I, Rudolf Foundation Clinic, 1030 Vienna, Austria
| | - Christine Brostjan
- Department of Surgery, Medical University of Vienna, General Hospital, 1090 Vienna, Austria
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6
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Hidalgo M, Martinez-Garcia M, Le Tourneau C, Massard C, Garralda E, Boni V, Taus A, Albanell J, Sablin MP, Alt M, Bahleda R, Varga A, Boetsch C, Franjkovic I, Heil F, Lahr A, Lechner K, Morel A, Nayak T, Rossomanno S, Smart K, Stubenrauch K, Krieter O. First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors. Clin Cancer Res 2017; 24:1536-1545. [PMID: 29217526 DOI: 10.1158/1078-0432.ccr-17-1588] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 10/23/2017] [Accepted: 11/30/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies.Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control.Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation.Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536-45. ©2017 AACR.
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Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. .,START Madrid-CIOCC, HM Sanchinarro, Madrid, Spain
| | | | | | | | | | | | - Alvaro Taus
- Medical Oncology Department, Hospital del Mar., Barcelona, Spain
| | - Joan Albanell
- Medical Oncology Department, Hospital del Mar., Barcelona, Spain
| | - Marie-Paule Sablin
- Department of Medical Oncology, Institut Curie, Saint-Cloud and Paris, France
| | - Marie Alt
- Department of Medical Oncology, Institut Curie, Saint-Cloud and Paris, France
| | - Ratislav Bahleda
- Department of Drug Development, Gustave Roussy, Villejuif, France
| | - Andrea Varga
- Department of Drug Development, Gustave Roussy, Villejuif, France
| | | | | | - Florian Heil
- Roche Innovation Center Munich, Penzberg, Germany
| | | | | | | | - Tapan Nayak
- Roche Innovation Center Basel, Basel, Switzerland
| | | | - Kevin Smart
- Roche Innovation Center Welwyn, Welwyn Garden City, United Kingdom
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Rohrs JA, Sulistio CD, Finley SD. Predictive model of thrombospondin-1 and vascular endothelial growth factor in breast tumor tissue. NPJ Syst Biol Appl 2016; 2. [PMID: 28713587 PMCID: PMC5507330 DOI: 10.1038/npjsba.2016.30] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Angiogenesis, the formation of new blood capillaries from pre-existing vessels, is a hallmark of cancer. Thus far, strategies for reducing tumor angiogenesis have focused on inhibiting pro-angiogenic factors, and less is known about the therapeutic effects of mimicking the actions of angiogenesis inhibitors. Thrombospondin-1 (TSP1) is an important endogenous inhibitor of angiogenesis that has been investigated as an anti-angiogenic agent. TSP1 impedes the growth of new blood vessels in many ways, including crosstalk with pro-angiogenic factors. Owing to the complexity of TSP1 signaling, a predictive systems biology model would provide quantitative understanding of the angiogenic balance in tumor tissue. Therefore, we have developed a molecular-detailed, mechanistic model of TSP1 and vascular endothelial growth factor (VEGF), a promoter of angiogenesis, in breast tumor tissue. The model predicts the distribution of the angiogenic factors in tumor tissue, revealing that TSP1 is primarily in an inactive, cleaved form owing to the action of proteases, rather than bound to its cellular receptors or to VEGF. The model also predicts the effects of enhancing TSP1’s interactions with its receptors and with VEGF. To provide additional predictions that can guide the development of new anti-angiogenic drugs, we simulate administration of exogenous TSP1 mimetics that bind specific targets. The model predicts that the CD47-binding TSP1 mimetic markedly decreases the ratio of receptor-bound VEGF to receptor-bound TSP1, in favor of anti-angiogenesis. Thus, we have established a model that provides a quantitative framework to study the response to TSP1 mimetics.
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Affiliation(s)
- Jennifer A Rohrs
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA
| | - Christopher D Sulistio
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA
| | - Stacey D Finley
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA.,Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA
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8
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Azzariti A, Porcelli L, Brunetti O, Del Re M, Longo V, Nardulli P, Signorile M, Xu JM, Calabrese A, Quatrale AE, Maiello E, Lorusso V, Silvestris N. Total and not bevacizumab-bound vascular endothelial growth factor as potential predictive factors to bevacizumab-based chemotherapy in colorectal cancer. World J Gastroenterol 2016; 22:6287-6295. [PMID: 27468218 PMCID: PMC4945987 DOI: 10.3748/wjg.v22.i27.6287] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 03/18/2016] [Accepted: 03/30/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify suitable biomarkers of response to bevacizumab (BV) - it remains an open question. The measurement of serum vascular endothelial growth factor (VEGF) has been proposed as a predictive factor for this drug, even if literature data are contradictory.
METHODS: We prospectively evaluated the role of BV, total and not BV-bound VEGF and angiopoietin-2 (Ang-2) serum levels as potential predictive factors of response for BV in combination with an oxaliplatin-based chemotherapy. BV, Ang-2, total and not BV-bound VEGF levels were measured at baseline, before 2nd and 5th cycle of oxaliplatin-based chemotherapy in 20 consecutive metastatic colorectal cancer patients.
RESULTS: Results were correlated to response to treatment. Variability in BV levels have been found, with decreased level in less responding patients. In particular, the concentration of BV increased of 3.96 ± 0.69 folds in serum of responsive patients after 3 more cycles of therapy compared to those with stable or progressive disease with a 0.72 ± 0.25 and 2.10 ± 0.13 fold increase, respectively. The determination of free and total VEGF demonstrated that the ratio between the two values, evaluated immediately before the 2nd and the 5th cycle of therapy, decreased from 26.65% ± 1.33% to 15.50% ± 3.47% in responsive patients and from 53.41% ± 4.75 to 34.95% ± 2.88% in those with stable disease. Conversely, in those with progression of disease, the ratio showed the opposite behavior coming up from 25.99% ± 5.23% to 51.71% ± 5.28%. The Ang-2 levels did not show any relationship.
CONCLUSION: Our data show that the ratio of not BV-bound VEGF to total VEGF serum and BV plasma concentrations for predicting the response to BV plus oxaliplatin-based chemotherapy could be a promising biomarker of response to BV.
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9
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Yan Y, Grothey A. Molecular profiling in the treatment of colorectal cancer: focus on regorafenib. Onco Targets Ther 2015; 8:2949-57. [PMID: 26508880 PMCID: PMC4610887 DOI: 10.2147/ott.s79145] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Metastatic colorectal cancer (mCRC) is a highly heterogeneous disease. Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies, including anti-EGFR antibodies, cetuximab and panitumumab, and VEGF inhibitors, bevacizumab, ramucirumab, and aflibercept. The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments, such as RAS mutation profiling for EGFR antibodies. Regorafenib is a multikinase inhibitor currently used as late line therapy for mCRC. The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized. Here, we review currently available clinical evidence of mCRC molecular profiling, such as RAS, BRAF, and MMR testing, and its role in targeted therapies with special focus on regorafenib treatment.
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Affiliation(s)
- Yiyi Yan
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Axel Grothey
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
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10
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Starlinger P, Haegele S, Wanek D, Zikeli S, Schauer D, Alidzanovic L, Fleischmann E, Gruenberger B, Gruenberger T, Brostjan C. Plasma thrombospondin 1 as a predictor of postoperative liver dysfunction. Br J Surg 2015; 102:826-36. [PMID: 25871570 DOI: 10.1002/bjs.9814] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/15/2015] [Accepted: 02/26/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Liver regeneration following liver resection involves a complex interplay of growth factors and their antagonists. Thrombospondin 1 has recently been identified as a critical inhibitor of liver regeneration by the activation of transforming growth factor β1 in mice, and preliminary data seem to confirm its relevance in humans. This study aimed to confirm these observations in an independent validation cohort. METHODS Perioperative circulating levels of thrombospondin 1 were measured in patients undergoing liver resection between January 2012 and September 2013. Postoperative liver dysfunction was defined according to the International Study Group of Liver Surgery and classification of morbidity was based on the criteria by Dindo et al. RESULTS In 85 patients (44 major and 41 minor liver resections), plasma levels of thrombospondin 1 increased 1 day after liver resection (mean 51·6 ng/ml before surgery and 68·3 ng/ml on postoperative day 1; P = 0·001). Circulating thrombospondin 1 concentration on the first postoperative day specifically predicted liver dysfunction (area under the receiver operating characteristic (ROC) curve 0·818, P = 0·003) and was confirmed as a significant predictor in multivariable analysis (Exp(B) 1·020, 95 per cent c.i. 1·005 to 1·035; P = 0·009). Patients with a high thrombospondin 1 concentration (over 80 ng/ml) on postoperative day 1 more frequently had postoperative liver dysfunction than those with a lower level (28 versus 2 per cent) and severe morbidity (44 versus 15 per cent), and their length of hospital stay was more than doubled (19·7 versus 9·9 days). CONCLUSION Thrombospondin 1 may prove a helpful clinical marker to predict postoperative liver dysfunction as early as postoperative day 1.
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Affiliation(s)
- P Starlinger
- Departments of Surgery, General Hospital, Vienna, Austria
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Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial. Br J Cancer 2015; 112:1314-25. [PMID: 25867261 PMCID: PMC4402460 DOI: 10.1038/bjc.2015.93] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 12/04/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Background: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT). Methods: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients. Results: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response. Conclusions: We could not support the ‘normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.
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12
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Parikh AA, Ni S, Koyama T, Pawlik TM, Penson D. Trends in the multimodality treatment of resectable colorectal liver metastases: an underutilized strategy. J Gastrointest Surg 2013; 17:1938-46. [PMID: 24018590 DOI: 10.1007/s11605-013-2325-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 08/17/2013] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Advances in multimodality therapy have led to increased survival for patients with metastatic colorectal cancer, but the impact on patients undergoing resection for colorectal liver metastases is unclear. The purpose of this study was to evaluate patterns of treatment for resectable colorectal liver metastases in the USA over the last two decades. METHODS Using the Surveillance, Epidemiology, and End Results-Medicare database, 1,926 patients who underwent hepatic resection for colorectal liver metastasis between 1991 and 2007 were included and divided into two cohorts: period 1 (1991-2000) and period 2 (2001-2007). Demographic data, treatment patterns, and outcomes of the two periods were compared by univariate methods. Multivariable regression models were constructed to predict the use of perioperative chemotherapy, postoperative complications, and 90-day mortality following liver resection. RESULTS The overall use of perioperative chemotherapy was 33 % and did not differ between periods, but shifted from postoperative to preoperative over time. By multivariable analysis, older age, black race, stage III primary cancer, and metachronous disease were predictive of lesser likelihood of chemotherapy use. The use of preoperative chemotherapy was not associated with any increase in perioperative morbidity or mortality. CONCLUSIONS Despite increased survival and widespread recommendations for the use of multimodality therapy, the overall resection rate and use of perioperative chemotherapy for resectable colorectal liver metastases remain underutilized and have not increased over time. Efforts to investigate barriers to the widespread use of multimodality therapy for these patients are warranted.
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Affiliation(s)
- Alexander A Parikh
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA,
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Custodio A, Barriuso J, de Castro J, Martínez-Marín V, Moreno V, Rodríguez-Salas N, Feliu J. Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: current evidence and future perspectives. Cancer Treat Rev 2013; 39:908-24. [PMID: 23510598 DOI: 10.1016/j.ctrv.2013.02.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2012] [Revised: 02/08/2013] [Accepted: 02/08/2013] [Indexed: 12/13/2022]
Abstract
Angiogenesis is a universal requirement for the growth of solid tumours beyond the limits of oxygen diffusion from the existing vasculature. The expression and function of proangiogenic and antiangiogenic factors are altered in solid malignancies to drive net neoangiogenesis. Vascular endothelial growth factor (VEGF) has been confirmed in several clinical trials as an important therapeutic target in colorectal cancer (CRC) treatment. However, given that the efficacy of antiangiogenic agents appears to be limited to a subset of patients, the identification of who will obtain the greater benefit from this therapy or suffer from specific toxicities and when or for how long they should be administered in the treatment algorithm are major open questions for clinicians and challenges for present and future research. Current evidence indicates some predictive value for particular circulating measures, such as an increase in VEGF, a decrease in vascular endothelial growth factor receptor 2 (VEGFR-2) or circulating endothelial cells, tissue biomarkers, microvessel density, KRAS and BRAF gene mutations or polymorphisms affecting components of the VEGF pathway. Many questions relating to these and other surrogate biomarkers, however, remain unanswered and their clinical usefulness has yet to be proven. This review will focus on the present status of knowledge and future perspectives for developing molecular tools to foresee and monitor antiangiogenic therapy activity in CRC patients.
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Affiliation(s)
- Ana Custodio
- Medical Oncology Department, IDiPAZ, RTICC (RD06/0020/1022), La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain.
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Starlinger P, Alidzanovic L, Schauer D, Maier T, Nemeth C, Perisanidis B, Tamandl D, Gruenberger B, Gruenberger T, Brostjan C. Neoadjuvant bevacizumab persistently inactivates VEGF at the time of surgery despite preoperative cessation. Br J Cancer 2012; 107:961-6. [PMID: 22850548 PMCID: PMC3464762 DOI: 10.1038/bjc.2012.342] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND When anti-VEGF (vascular endothelial growth factor) antibody bevacizumab is applied in neoadjuvant treatment of colorectal cancer patients with liver metastasis, 5-6 weeks between last bevacizumab dose and liver resection are currently recommended to avoid complications in wound and liver regeneration. In this context, we aimed to determine whether VEGF is inactivated by bevacizumab at the time of surgery. METHODS Fifty colorectal cancer patients with liver metastases received neoadjuvant chemotherapy ± bevacizumab supplementation. The last dose of bevacizumab was administered 6 weeks before surgery. Plasma, subcutaneous and intraabdominal wound fluid were analysed for VEGF content before and after liver resection (day 1-3). Immunoprecipitation was applied to determine the amount of bevacizumab-bound VEGF. RESULTS Bevacizumab-treated individuals showed no increase in perioperative complications. During the entire monitoring period, plasma VEGF was inactivated by bevacizumab. In wound fluid, VEGF was also completely bound by bevacizumab and was remarkably low compared with the control chemotherapy group. CONCLUSION These data document that following a cessation time of 6 weeks, bevacizumab is fully active and blocks circulating and local VEGF at the time of liver resection. However, despite effective VEGF inactivation no increase in perioperative morbidity is recorded suggesting that VEGF activity is not essential in the immediate postoperative recovery period.
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Affiliation(s)
- P Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Discrimination between circulating endothelial cells and blood cell populations with overlapping phenotype reveals distinct regulation and predictive potential in cancer therapy. Neoplasia 2012; 13:980-90. [PMID: 22028623 DOI: 10.1593/neo.11916] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Revised: 08/28/2011] [Accepted: 09/06/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Circulating endothelial cells (CECs) have been proposed to predict patient response to antiangiogenic cancer therapy. However, contradictory reports and inconsistency in the phenotypic identification of CECs have led us to compare three cell populations with partially overlapping phenotype in cancer patients receiving chemotherapy and the antiangiogenic agent bevacizumab. METHODS Patients (n = 20) with locally advanced pancreatic cancer were monitored during 16 weeks of neoadjuvant treatment with gemcitabine and bevacizumab. Detection of circulating cell populations was based on the marker combination CD45, CD31, and CD146; levels of viable and dead (7-aminoactinomycin D-positive) cells were evaluated by flow cytometry in 2-week intervals. RESULTS We were able to discriminate and concomitantly monitor three cell populations elevated in cancer patients. Whereas CECs were defined as CD45(-) CD31(+) CD146(+), the distinct populations of CD45(-) CD31(-) CD146(+) and CD45(-) CD31(high) CD146(-) cells were partly positive for CD3 and CD41, respectively. CECs and CD45(-) CD31(-) CD146(+) cells increased during therapy; the rise in dead cells was positively correlated with patient response or survival. Conversely, CD45(-) CD31(high) CD146(-) cells decreased in neoadjuvant treatment. A highly significant correlation was established for improved patient response and a minor decrease in viable cell counts. CONCLUSIONS Flow cytometric CEC analysis based on CD45, CD31, and CD146 requires careful discrimination between blood cell populations with overlapping phenotype showing hallmarks of activated T cells and large platelets. However, these three cell populations show distinct regulation during cancer therapy, and their concomitant analysis may offer extended prognostic and predictive information.
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Myelosuppression of thrombocytes and monocytes is associated with a lack of synergy between chemotherapy and anti-VEGF treatment. Neoplasia 2011; 13:419-27. [PMID: 21532882 DOI: 10.1593/neo.101508] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 01/30/2011] [Accepted: 02/08/2011] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Chemotherapeutic agents that have shown improved patient outcome when combined with anti-vascular endothelial growth factor (VEGF) therapy were recently identified to induce the mobilization of proangiogenic Tie-2-expressing monocytes (TEMs) and endothelial progenitor cells (EPCs) by platelet release of stromal cell-derived factor 1α (SDF-1α). VEGF blockade was found to counteract cell mobilization. We aimed to determine why agents like gemcitabine do not elicit TEM and EPC recruitment and may therefore lack synergy with anti-VEGF therapy. EXPERIMENTAL DESIGN Locally advanced pancreatic cancer patients (n = 20) were monitored during 16 weeks of neoadjuvant therapy. Treatment was based on gemcitabine with or without the addition of bevacizumab. Blood levels of proangiogenic cell populations and angiogenesis factors were determined in 2-week intervals. RESULTS The lack of EPC mobilization during gemcitabine therapy was associated with severe thrombocytopenia and reduced SDF-1α blood concentrations. Furthermore, myelosuppression by gemcitabine correlated significantly with loss of TEMs. With respect to angiogenic factors stored and released by platelets, plasma levels of the angiogenesis inhibitor thrombospondin 1 (TSP-1) were selectively decreased and correlated significantly with thrombocytopenia in response to gemcitabine therapy. CONCLUSIONS A thorough literature screen identified thrombocytopenia as a common feature of chemotherapeutic agents that lack synergy with anti-VEGF treatment. Our results on gemcitabine therapy indicate that myelosuppression (in particular, with respect to thrombocytes and monocytes) interferes with the mobilization of proangiogenic cell types targeted by bevacizumab and may further counteract antiangiogenic therapy by substantially reducing the angiogenesis inhibitor TSP-1.
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Abstract
Angiogenesis is a crucial component of tumor growth and metastasis. Targeting the vascular endothelial growth factor pathway represents therapeutic potentials for treating cancer. To date, 3 Food and Drug Administration-approved agents targeting angiogenesis have been developed, bevacizumab, sunitinib, and sorafenib. However, no validated biomarkers are available to identify those patients who are likely to benefit from antiangiogenesis therapy. Molecular biomarker research in antiangiogenesis inhibition is an actively growing field. Although current data are extremely promising, it is still uncertain which biomarker(s) can reliably predict their efficacy. With increasing numbers of inhibitors being developed, the need for biomarkers is more critical than ever. This review will focus on translational research that strives to identify molecular biomarkers (tissue, circulating and genomic) for approved antiangiogenesis therapies that can indicate benefit, resistance, and toxicity.
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Loupakis F, Cremolini C, Fioravanti A, Orlandi P, Salvatore L, Masi G, Di Desidero T, Canu B, Schirripa M, Frumento P, Di Paolo A, Danesi R, Falcone A, Bocci G. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer 2011; 104:1262-9. [PMID: 21407216 PMCID: PMC3078596 DOI: 10.1038/bjc.2011.85] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background: The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC). Methods: Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: −2578A/C, −1498C/T, −1154A/G, −634C/G and 936C/T; and VEGFR-2: −604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients. Results: Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found. Conclusion: Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.
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Affiliation(s)
- F Loupakis
- Unit of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma, 67, Pisa, 56126, Italy
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Abstract
Bevacizumab is a monoclonal antibody against vascular endothelial growth factor that has antiangiogenic activity and improves progression-free survival in many solid malignancies when combined with cytotoxic chemotherapy, but has little effect on overall survival. Despite the effects of this drug in unselected patients, the Response Evaluation Criteria in Solid Tumours are suboptimum to predict benefit. Additionally, tumours show inherent and emerging resistance to regimens that include bevacizumab. The ability to target therapy towards well selected subgroups of patients would increase the likelihood of benefits and would improve cost-effectiveness and therapeutic outcomes. In this review we discuss putative clinical, radiological, and molecular markers of bevacizumab efficacy, derived from data obtained in clinical trials. Current evidence indicates some predictive value for hypertension, vascular imaging, and polymorphisms affecting components of the vascular endothelial growth factor pathway in patients receiving bevacizumab. Many questions relating to these and other surrogate biomarkers, however, remain unanswered and their clinical usefulness has yet to be proven.
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Affiliation(s)
- Adrian M Jubb
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Pavlidis ET, Ballas KD, Symeonidis NG, Psarras K, Koliakos G, Kouzi-Koliakos K, Topouridou K, Rafailidis SF, Pavlidis TE, Marakis GN, Sakantamis AK. The effect of bevacizumab on colon anastomotic healing in rats. Int J Colorectal Dis 2010; 25:1465-73. [PMID: 20689957 DOI: 10.1007/s00384-010-1039-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2010] [Indexed: 02/05/2023]
Abstract
PURPOSE The aim of the study was to investigate the effect of angiogenesis inhibition by bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF) antibody, on the healing process of colonic anastomoses in rats, assessing some specific involved factors. This new agent is used mainly in metastatic colorectal cancer. The angiogenesis plays an important role in both wound healing and metastatic invasion and spread of malignant cells. There has not been any evidence assessing the optimal time for its safe use in operated patients. MATERIALS AND METHODS Forty Wistar rats were randomly allocated into four equal groups. A colonic anastomosis was performed in all rats. Half of them received intraoperatively a single dose of bevacizumab 5 mg/body weight and the rest received placebo. The animals were sacrificed on the 7th (Avastin 7th, placebo 7th) and 14th (Avastin 14th, placebo 14th) postoperative day. The anastomosis was resected and sent for histological study and for tissue biochemical assays (VEGF, endothelin-1 (ET-1), C-reactive protein (CRP), pro-oxidant-antioxidant balance (PAB), carbonylated proteins, hydroxyproline) using specific enzyme-linked immunosorbent assay kits. For statistical analysis, the Mann-Whitney U test was used (of statistical significance when P < 0.05). RESULTS No complication or anastomotic dehiscence was observed. Histology did not reveal statistically significant differences between groups concerning degree of inflammation, fibroblasts, collagen, and fibrosis. Likewise, hydroxyproline levels did not differ. However, some statistically significant differences were found in VEGF, CRP and carbonyl proteins (Avastin 7th vs placebo 7th, placebo 14th vs placebo 7th), ET-1, and PAB (Avastin 14th vs Avastin 7th), which did not finally affect the collagen synthesis marker hydroxyproline, nor did the anastomotic strength. CONCLUSIONS Bevacizumab, when administered intraoperatively, has no significant effect on colon anastomotic healing in rats despite a transient mild ischemia.
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Affiliation(s)
- Efstathios T Pavlidis
- Second Propedeutical Department of Surgery, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Konstantinoupoleos 49, 546 42, Thessaloniki, Greece
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Intracellular bevacizumab reduces phagocytotic uptake in RPE cells. Graefes Arch Clin Exp Ophthalmol 2010; 248:819-24. [DOI: 10.1007/s00417-010-1317-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Revised: 01/22/2010] [Accepted: 01/25/2010] [Indexed: 10/19/2022] Open
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Starlinger P, Gebhardt K, Grünberger T, Brostjan C. Systemic effects of anti-VEGF therapy – Mini-review. Eur Surg 2010. [DOI: 10.1007/s10353-010-0513-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Klinger M, Eipeldauer S, Hacker S, Herberger B, Tamandl D, Dorfmeister M, Koelblinger C, Gruenberger B, Gruenberger T. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol 2009; 35:515-20. [PMID: 19200687 DOI: 10.1016/j.ejso.2008.12.013] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 12/19/2008] [Accepted: 12/23/2008] [Indexed: 01/16/2023] Open
Abstract
AIM In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited. METHODS Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone. CONCLUSIONS This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.
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Affiliation(s)
- M Klinger
- Department of General Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
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Colorectal Cancer Liver Metastases: Neoadjuvant Therapy with Bevacizumab. COLORECTAL CANCER 2009. [DOI: 10.1007/978-1-4020-9545-0_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Using bevacizumab and cetuximab before liver surgery. CURRENT COLORECTAL CANCER REPORTS 2008. [DOI: 10.1007/s11888-008-0021-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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