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Patel SA, Nilsson MB, Le X, Cascone T, Jain RK, Heymach JV. Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy. Clin Cancer Res 2023; 29:30-39. [PMID: 35969170 DOI: 10.1158/1078-0432.ccr-22-1366] [Citation(s) in RCA: 184] [Impact Index Per Article: 92.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/28/2022] [Accepted: 08/03/2022] [Indexed: 02/06/2023]
Abstract
Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently "normalize" tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.
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Affiliation(s)
- Sonia A Patel
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Monique B Nilsson
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiuning Le
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina Cascone
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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Oudard S, Benhamouda N, Escudier B, Ravel P, Tran T, Levionnois E, Negrier S, Barthelemy P, Berdah JF, Gross-Goupil M, Sternberg CN, Bono P, Porta C, Giorgi UD, Parikh O, Hawkins R, Highley M, Wilke J, Decker T, Tanchot C, Gey A, Terme M, Tartour E. Decrease of Pro-Angiogenic Monocytes Predicts Clinical Response to Anti-Angiogenic Treatment in Patients with Metastatic Renal Cell Carcinoma. Cells 2021; 11:17. [PMID: 35011579 PMCID: PMC8750389 DOI: 10.3390/cells11010017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/06/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
The modulation of subpopulations of pro-angiogenic monocytes (VEGFR-1+CD14 and Tie2+CD14) was analyzed in an ancillary study from the prospective PazopanIb versus Sunitinib patient preferenCE Study (PISCES) (NCT01064310), where metastatic renal cell carcinoma (mRCC) patients were treated with two anti-angiogenic drugs, either sunitinib or pazopanib. Blood samples from 86 patients were collected prospectively at baseline (T1), and at 10 weeks (T2) and 20 weeks (T3) after starting anti-angiogenic therapy. Various subpopulations of myeloid cells (monocytes, VEGFR-1+CD14 and Tie2+CD14 cells) decreased during treatment. When patients were divided into two subgroups with a decrease (defined as a >20% reduction from baseline value) (group 1) or not (group 2) at T3 for VEGFR-1+CD14 cells, group 1 patients presented a median PFS and OS of 24 months and 37 months, respectively, compared with a median PFS of 9 months (p = 0.032) and a median OS of 16 months (p = 0.033) in group 2 patients. The reduction in Tie2+CD14 at T3 predicted a benefit in OS at 18 months after therapy (p = 0.04). In conclusion, in this prospective clinical trial, a significant decrease in subpopulations of pro-angiogenic monocytes was associated with clinical response to anti-angiogenic drugs in patients with mRCC.
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Affiliation(s)
- Stephane Oudard
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
- APHP, Service de Cancérologie, Hôpital Européen Georges Pompidou, Université de Paris, 75908 Paris, France
| | - Nadine Benhamouda
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
| | - Bernard Escudier
- Department of Medical Oncology, Institut Gustave Roussy, CEDEX, 94805 Villejuif, France;
| | - Patrice Ravel
- Cancer Bioinformatics and Systems Biology, Institut de Recherche en Cancérologie de Montpellier, Campus Val d’Aurelle, Université Montpellier, CEDEX 5, 34298 Montpellier, France;
| | - Thi Tran
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
| | - Emeline Levionnois
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
| | - Sylvie Negrier
- Centre Léon Bérard Lyon, University Lyon 1, 69008 Lyon, France;
| | - Philippe Barthelemy
- Institut de Cancérologie Strasbourg Europe, Strasbourg University Hospital, 67200 Strasbourg, France;
| | - Jean François Berdah
- Medical Oncology Unit, Hôpital Privé Toulon-Hyères, Sainte-Marguerite, 83400 Hyeres, France;
| | - Marine Gross-Goupil
- Department of Medical Oncology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, 31000 Bordeaux, France;
| | - Cora N. Sternberg
- Englander Institute for Precision Medicine, Weill Cornell Medicine, Sandra and Edward Meyer Cancer, New York, NY 10065, USA;
| | - Petri Bono
- Kamppi Hospital Department, Terveystalo Finland, 00100 Helsinki, Finland;
| | - Camillo Porta
- Division of Translational Oncology, IRCCS San Matteo University Hospital, 27100 Pavia, Italy;
- Division of Oncology, Policlinico Consorziale di Bari, University of Bari ‘A. Moro’, 70121 Bari, Italy
| | - Ugo De Giorgi
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, 47014 Meldola, Italy;
| | - Omi Parikh
- Department of Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston PR2 9HT, UK;
| | - Robert Hawkins
- Institute of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK;
| | - Martin Highley
- Oncology Centre, Derriford Hospital, Plymouth PL6 8DH, UK;
| | - Jochen Wilke
- Gemeinschaftspraxis Dres. Wilke/Wagner/Petzoldt, 90766 Fuerth, Germany;
| | - Thomas Decker
- Studienzentrum Onkologie, Practice for Hematology and Oncology, 88212 Ravensburg, Germany;
| | - Corinne Tanchot
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
| | - Alain Gey
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
| | - Magali Terme
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
| | - Eric Tartour
- APHP, Hôpital Européen Georges Pompidou, INSERM U970, PARCC, Université de Paris, 75020 Paris, France; (N.B.); (T.T.); (E.L.); (C.T.); (A.G.); (M.T.)
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Di Paolo V, Colletti M, Ferruzzi V, Russo I, Galardi A, Alessi I, Milano GM, Di Giannatale A. Circulating Biomarkers for Tumor Angiogenesis: Where Are We? Curr Med Chem 2020; 27:2361-2380. [PMID: 30129403 DOI: 10.2174/0929867325666180821151409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 01/26/2023]
Abstract
BACKGROUND In recent years, several anti-angiogenic drugs have been developed and their addition to standard treatment has been associated with clinical benefits. However, the response to anti-angiogenic therapy is characterized by considerable variability. In this context, the development of dynamic non-invasive biomarkers would be helpful to elucidate the emergence of anti-angiogenic resistance as well as to correctly address the treatment. OBJECTIVES The purpose of this review is to describe current reports on circulating diagnostic and prognostic biomarkers related to angiogenesis. We further discuss how this non-invasive strategy could improve the monitoring of tumor treatment and help clinical strategy. RESULTS We discuss the latest evidence in the literature regarding circulating anti-angiogenic markers. Besides growth factor proteins, different circulating miRNAs could exert a pro- or anti-angiogenic activity so as to represent suitable candidates for a non-invasive strategy. Recent reports indicate that tumor-derived exosomes, which are small membrane vesicles abundant in biological fluids, also have an impact on vascular remodeling. CONCLUSION Numerous circulating biomarkers related to angiogenesis have been recently identified. Their use will allow identifying patients who are more likely to benefit from a specific anti-angiogenic treatment, as well as detecting those who will develop resistance and/or adverse effects. Nonetheless, further studies are required to elucidate the role of these biomarkers in clinical settings.
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Affiliation(s)
- Virginia Di Paolo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Marta Colletti
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Valentina Ferruzzi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Ida Russo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Angela Galardi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Iside Alessi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Giuseppe Maria Milano
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Angela Di Giannatale
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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Wilding CP, Elms ML, Judson I, Tan AC, Jones RL, Huang PH. The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib. Expert Rev Anticancer Ther 2019; 19:971-991. [PMID: 31665941 PMCID: PMC6882314 DOI: 10.1080/14737140.2019.1686979] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/28/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.Areas covered: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.Expert opinion: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease.
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Affiliation(s)
| | - Mark L Elms
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Ian Judson
- Department of Medical Oncology, Sarcoma Unit, The Royal Marsden Hospital, London, UK
| | - Aik-Choon Tan
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Robin L Jones
- Department of Medical Oncology, Sarcoma Unit, The Royal Marsden Hospital, London, UK
| | - Paul H Huang
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
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Pokuri VK, Tomaszewski GM, Ait-Oudhia S, Groman A, Khushalani NI, Lugade AA, Thanavala Y, Ashton EA, Grande C, Fetterly GJ, Iyer R. Efficacy, Safety, and Potential Biomarkers of Sunitinib and Transarterial Chemoembolization (TACE) Combination in Advanced Hepatocellular Carcinoma (HCC): Phase II Trial. Am J Clin Oncol 2019; 41:332-338. [PMID: 27014931 DOI: 10.1097/coc.0000000000000286] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To evaluate the safety/efficacy and explore biomarkers for a rationally designed combination of sunitinib and transarterial chemoembolization (TACE) in a prospective phase 2 study of advanced hepatocellular carcinoma (HCC). METHODS Inoperable HCC patients with Child-Pugh A disease received 37.5 mg sunitinib from days 1 to 7 followed by TACE on day 8. Sunitinib was resumed from days 15 to 36 followed by 2 weeks off. Patients received subsequent sunitinib cycles of 4 weeks on and 2 weeks off. Dynamic contrast-enhanced magnetic resonance imaging and circulating soluble biomarkers were assessed at baseline, day 8, day 10, and day 36. RESULTS Sixteen patients with liver only (n=10) and extrahepatic disease (n=6) were enrolled. After a median follow-up of 12.8 months, 2 partial responses, 11 stable disease, and 3 clinical deteriorations were seen for a clinical benefit rate of 81%. Median progression-free survival (PFS) was 8 months (95% CI, 4.3-9.3) and overall survival was 14.9 months (95% CI, 6.3-27.1). Eleven of 16 patients (69%) had grade 3/4 toxicities attributable to sunitinib, the most frequent being thrombocytopenia, amylase/lipase elevations, lymphopenia, and fatigue. Mean K (volume transfer constant) and viable tumor percent in consented patients decreased by 27% and 14.8%, respectively, with combination therapy. Soluble vascular endothelial growth factor receptor-2 (sVEGFR2) levels, cytokines (interleukin-8, interleukin-21), and monocytes decreased with combination therapy. Estimated sunitinib IC50 values of 15 and 10 ng/mL modulated K and AUC90. sVEGFR2 levels decreased with K and AUC90. CONCLUSIONS Encouraging progression-free survival and overall survival were seen with acceptable toxicity in our study of sunitinib and TACE combination in advanced HCC. Potential imaging and serum biomarkers showed increased benefit with combination therapy.
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Affiliation(s)
| | | | - Sihem Ait-Oudhia
- Pharmacometrics and Systems Pharmacology at Lake Nona, University of Florida, Orlando, FL
| | | | | | - Amit A Lugade
- Center for Immunotherapy, Roswell Park Cancer Institute (RPCI), Buffalo
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Ronellenfitsch U, Karampinis I, Dimitrakopoulou-Strauss A, Sachpekidis C, Jakob J, Kasper B, Nowak K, Pilz L, Attenberger U, Gaiser T, Derigs HG, Schwarzbach M, Hohenberger P. Preoperative Pazopanib in High-Risk Soft Tissue Sarcoma: Phase II Window-of Opportunity Study of the German Interdisciplinary Sarcoma Group (NOPASS/GISG-04). Ann Surg Oncol 2019; 26:1332-1339. [DOI: 10.1245/s10434-019-07183-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Indexed: 11/18/2022]
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Martins D, Spada F, Lambrescu I, Rubino M, Cella C, Gibelli B, Grana C, Ribero D, Bertani E, Ravizza D, Bonomo G, Funicelli L, Pisa E, Zerini D, Fazio N. Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors. Target Oncol 2017; 12:611-622. [PMID: 28634872 DOI: 10.1007/s11523-017-0506-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.
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Affiliation(s)
- Diana Martins
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy
| | - Francesca Spada
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy
| | - Ioana Lambrescu
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy
| | - Manila Rubino
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy
| | - Chiara Cella
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy
| | - Bianca Gibelli
- Division of Otolaryngology-Head and Neck Surgery, European Institute of Oncology, IEO, Milan, Italy
| | - Chiara Grana
- Division of Nuclear Medicine, European Institute of Oncology, IEO, Milan, Italy
| | - Dario Ribero
- Division of Hepatobiliopancreatic Surgery, European Institute of Oncology, IEO, Milan, Italy
| | - Emilio Bertani
- Division of Hepatobiliopancreatic Surgery, European Institute of Oncology, IEO, Milan, Italy
| | - Davide Ravizza
- Division of Endoscopy, European Institute of Oncology, IEO, Milan, Italy
| | - Guido Bonomo
- Division of Interventional Radiology, European Institute of Oncology, IEO, Milan, Italy
| | - Luigi Funicelli
- Division of Radiology, European Institute of Oncology, IEO, Milan, Italy
| | - Eleonora Pisa
- Division of Pathology, European Institute of Oncology, IEO, Milan, Italy
| | - Dario Zerini
- Division of Radiotherapy, European Institute of Oncology, IEO, Milan, Italy
| | - Nicola Fazio
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy.
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Diekstra MH, Fritsch A, Kanefendt F, Swen JJ, Moes D, Sörgel F, Kinzig M, Stelzer C, Schindele D, Gauler T, Hauser S, Houtsma D, Roessler M, Moritz B, Mross K, Bergmann L, Oosterwijk E, Kiemeney LA, Guchelaar HJ, Jaehde U. Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2017; 6:604-613. [PMID: 28571114 PMCID: PMC5613186 DOI: 10.1002/psp4.12210] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/01/2017] [Accepted: 05/13/2017] [Indexed: 12/15/2022]
Abstract
The tyrosine kinase inhibitor sunitinib is used as first‐line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed‐dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR‐2 and sVEGFR‐3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C‐II‐005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time‐to‐event (TTE) models. Baseline sVEGFR‐2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD‐guided strategies for the individualization of anti‐angiogenic therapies.
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Affiliation(s)
- M H Diekstra
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - A Fritsch
- Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
| | - F Kanefendt
- Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
| | - J J Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Djar Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - F Sörgel
- IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany
| | - M Kinzig
- IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany
| | - C Stelzer
- IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany
| | - D Schindele
- Department for Urology and Paediatric Urology, University of Magdeburg, Magdeburg, Germany
| | - T Gauler
- West German Cancer Center, University Hospital Essen, Essen, Germany
| | - S Hauser
- Department of Urology, University Hospital Bonn, Bonn, Germany
| | - D Houtsma
- Haga Hospital, Den Haag, The Netherlands
| | | | - B Moritz
- CESAR Central Office, Vienna, Austria
| | - K Mross
- Department of Medical Oncology, Tumor Biology Center Freiburg, Freiburg, Germany
| | - L Bergmann
- Cancer-Center Rhein-Main, University Hospital Frankfurt, Frankfurt, Germany
| | - E Oosterwijk
- Department of Urology, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - L A Kiemeney
- Department of Epidemiology and Biostatistics, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - H J Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - U Jaehde
- Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
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Aparicio LMA, Fernandez IP, Cassinello J. Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy. Clin Transl Oncol 2017; 19:1175-1182. [PMID: 28409322 PMCID: PMC5599454 DOI: 10.1007/s12094-017-1657-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/25/2017] [Indexed: 12/18/2022]
Abstract
The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy.
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Affiliation(s)
- L M A Aparicio
- Medical Oncology Department, Hospital Universitario A Coruña, Xubias s/n, 15615, La Coruña, Spain.
| | - I P Fernandez
- Medical Oncology Department, Hospital Universitario de Cabueñes, Gijón, Spain
| | - J Cassinello
- Medical Oncology Department, Hospital Universitario de Guadalajara, Guadalajara, Spain
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Lapeyre-Prost A, Terme M, Pernot S, Pointet AL, Voron T, Tartour E, Taieb J. Immunomodulatory Activity of VEGF in Cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 330:295-342. [PMID: 28215534 DOI: 10.1016/bs.ircmb.2016.09.007] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ability of tumor cells to escape tumor immunosurveillance contributes to cancer development. Factors produced in the tumor microenvironment create "tolerizing" conditions and thereby help the tumor to evade antitumoral immune responses. VEGF-A, already known for its major role in tumor vessel growth (neoangiogenesis), was recently identified as a key factor in tumor-induced immunosuppression. In particular, VEGF-A fosters the proliferation of immunosuppressive cells, limits T-cell recruitment into tumors, and promotes T-cell exhaustion. Antiangiogenic therapies have shown significant efficacy in patients with a variety of solid tumors, preventing tumor progression by limiting tumor-induced angiogenesis. VEGF-targeting therapies have also been shown to modulate the tumor-induced immunosuppressive microenvironment, enhancing Th1-type T-cell responses and increasing tumor infiltration by T cells. The immunomodulatory properties of VEGF-targeting therapies open up new perspectives for cancer treatment, especially through strategies combining antiangiogenic drugs with immunotherapy. Preclinical models and early clinical studies of these combined approaches have given promising results.
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Affiliation(s)
- A Lapeyre-Prost
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France
| | - M Terme
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France.
| | - S Pernot
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France
| | - A-L Pointet
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France
| | - T Voron
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service de chirurgie digestive, Hôpital Européen Georges Pompidou, Paris, France
| | - E Tartour
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'immunologie biologique. Hôpital Européen Georges Pompidou, Paris, France
| | - J Taieb
- INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Paris, France; Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France.
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11
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Kao J, Timmins J, Ozao-Choy J, Packer S. Effects of combined sunitinib and extracranial stereotactic radiotherapy on bone marrow hematopoiesis. Oncol Lett 2016; 12:2139-2144. [PMID: 27602153 DOI: 10.3892/ol.2016.4851] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 06/02/2016] [Indexed: 12/17/2022] Open
Abstract
There is considerable interest in deploying stereotactic body radiotherapy in combination with immune therapy for patients with extracranial oligometastases. In addition to angiogenesis inhibition, sunitinib appears to mediate antitumor immunity through effects on circulating monocytic cells. The current study investigated the effects of combined sunitinib and stereotactic radiotherapy on hematopoiesis. As part of a phase I/II clinical trial utilizing concurrent sunitinib (25-50 mg on days 1-28) and image-guided radiation therapy (40-50 Gy in 10 fractions starting on days 8-19) for patients with metastatic cancer, the complete blood count, platelet count and automatic differential were performed pretreatment and on days 8 and 19. On average, sunitinib monotherapy for 7 days resulted in a 33% decrease in monocytes and an 18% decrease in neutrophils (P<0.01 for all). Compared to sunitinib alone, combined sunitinib and radiation resulted in a further decrease in neutrophils, lymphocytes and platelets (P<0.05). Following sunitinib and radiation treatment, a greater than average decrease in monocytes (≥200/µl) was associated with a significant increase in progression-free and overall survival times. This exploratory study provides further evidence that monocytes represent a potential biomarker in patients with solid tumors treated with sunitinib.
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Affiliation(s)
- Johnny Kao
- Department of Radiation Oncology, Good Samaritan Hospital Medical Center, West Islip, NY 11795, USA; Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Jonathan Timmins
- Department of Radiation Oncology, Good Samaritan Hospital Medical Center, West Islip, NY 11795, USA
| | - Junko Ozao-Choy
- Department of Surgery, University of California, Los Angeles (UCLA) Medical Center, Los Angeles, CA 90502, USA
| | - Stuart Packer
- Division of Medical Oncology, Mount Sinai School of Medicine, New York, NY 10029, USA
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12
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Zahran AM, Aly SS, Altayeb HA, Ali AM. Circulating endothelial cells and their progenitors in acute myeloid leukemia. Oncol Lett 2016; 12:1965-1970. [PMID: 27602121 DOI: 10.3892/ol.2016.4859] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 06/16/2016] [Indexed: 12/15/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the accumulation of immature myeloid progenitor cells in the bone marrow. Studies are required to investigate the prognostic and predictive value of surrogate biomarkers. Given the importance of angiogenesis in oncology in terms of pathogenesis as well as being a target for treatment, circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) are promising candidates to serve as such markers. The aim of the present study was to quantify CECs and EPCs in patients with AML at initial diagnosis and following induction chemotherapy, and to correlate these findings with the response to treatment in AML patients. The present study included 40 patients with de novo AML and 20 age- and gender-matched healthy controls. CECs and EPCs were evaluated by flow cytometry at initial diagnosis and after induction chemotherapy (3+7 protocol for AML other than M3 and all-trans-retinoic acid plus anthracycline for M3 disease). CECs and EPCs were significantly higher in AML patients at diagnosis and after induction chemotherapy than in controls. After induction chemotherapy, CECs and EPCs were significantly decreased compared with the levels at initial diagnosis. Patients who achieved complete response (n=28) had lower initial CEC and EPC levels compared with patients who did not respond to treatment. These results suggest that CEC levels are higher in AML patients and may correlate with disease status and treatment response. Further investigations are required to better determine the predictive value and implication of these cells in AML management.
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Affiliation(s)
- Asmaa Mohammed Zahran
- Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
| | - Sanaa Shaker Aly
- Department of Clinical Pathology, Faculty of Medicine, South Valley University, Qena 83523, Egypt
| | - Hanan Ahmed Altayeb
- Department of Medical Oncology, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
| | - Arwa Mohammed Ali
- Department of Medical Oncology, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
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13
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Ait-Oudhia S, Mager DE, Pokuri V, Tomaszewski G, Groman A, Zagst P, Fetterly G, Iyer R. Bridging Sunitinib Exposure to Time-to-Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2016; 5:297-304. [PMID: 27300260 PMCID: PMC5131886 DOI: 10.1002/psp4.12084] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 04/18/2016] [Indexed: 12/31/2022]
Abstract
Hepatocellular carcinoma (HCC) is third in cancer-related causes of death worldwide and its treatment is a significant unmet medical need. Sunitinib is a selective tyrosine kinase inhibitor of the angiogenic biomarker: soluble vascular endothelial growth factor receptor-2 (sVEGFR2 ). Sunitinib failed its primary overall survival endpoint in patients with advanced HCC in a phase III trial compared to sorafenib. In the present study, pharmacokinetic-pharmacodynamic modeling was used to link drug-exposure to tumor-growth-inhibition (TGI) and time-to-tumor progression (TTP) through sVEGFR2 dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR2 and that such inhibition is associated with TGI, and 2) daily sVEGFR2 exposure is likely a reliable predictor for the TTP in HCC patients. Moreover, the model quantitatively links the dynamics of an angiogenesis biomarker to TTP and accurately predicts observed literature-reported results of placebo treatment.
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Affiliation(s)
- S Ait-Oudhia
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
| | - D E Mager
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
| | - V Pokuri
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - G Tomaszewski
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - A Groman
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - P Zagst
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - G Fetterly
- Clinical Pharmacology and Regulatory Affairs, Buffalo, New York, USA
| | - R Iyer
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA
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14
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Cidon EU, Alonso P, Masters B. Markers of Response to Antiangiogenic Therapies in Colorectal Cancer: Where Are We Now and What Should Be Next? Clin Med Insights Oncol 2016; 10:41-55. [PMID: 27147901 PMCID: PMC4849423 DOI: 10.4137/cmo.s34542] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/15/2016] [Accepted: 03/13/2016] [Indexed: 12/17/2022] Open
Abstract
Despite advances in the treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the Western world. Angiogenesis is a complex process that involves the formation of new blood vessels from preexisting vessels. It is essential for promoting cancer survival, growth, and dissemination. The inhibition of angiogenesis has been shown to prevent tumor progression experimentally, and several chemotherapeutic targets of tumor angiogenesis have been identified. These include anti-vascular endothelial growth factor (VEGF) treatments, such as bevacizumab (a VEGF-specific binding antibody) and anti-VEGF receptor tyrosine kinase inhibitors, although antiangiogenic therapy has been shown to be effective in the treatment of several cancers, including CRC. However, it is also associated with its own side effects and financial costs. Therefore, the identification of biomarkers that are able to identify patients who are more likely to benefit from antiangiogenic treatment is very important. This article intends to be a concise summary of the potential biomarkers that can predict or prognosticate the benefit of antiangiogenic treatments in CRC, and also what we can expect in the near future.
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Affiliation(s)
- E. Una Cidon
- Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK
| | - P. Alonso
- Department of Clinical Oncology, Clinical University Hospital, Valladolid, Spain
| | - B. Masters
- Department of Oncology, Nottingham City Hospital, Nottingham, UK
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15
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Shaked Y. Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Nat Rev Clin Oncol 2016; 13:611-26. [PMID: 27118493 DOI: 10.1038/nrclinonc.2016.57] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Local and systemic treatments for cancer include surgery, radiation, chemotherapy, hormonal therapy, molecularly targeted therapies, antiangiogenic therapy, and immunotherapy. Many of these therapies can be curative in patients with early stage disease, but much less frequently is this the case when they are used to treat advanced-stage metastatic disease. In the latter setting, innate and/or acquired resistance are among the reasons for reduced responsiveness or nonresponsiveness to therapy, or for tumour relapse after an initial response. Most studies of resistance or reduced responsiveness focus on 'driver' genetic (or epigenetic) changes in the tumour-cell population. Several studies have highlighted the contribution of therapy-induced physiological changes in host tissues and cells that can reduce or even nullify the desired antitumour effects of therapy. These unwanted host effects can promote tumour-cell proliferation (repopulation) and even malignant aggressiveness. These effects occur as a result of systemic release of numerous cytokines, and mobilization of various host accessory cells, which can invade the treated tumour microenvironment. In short, the desired tumour-targeting effects of therapy (the 'yin') can be offset by a reactive host response (the 'yang'); proactively preventing or actively suppressing the latter represents a possible new approach to improving the efficacy of both local and systemic cancer therapies.
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Affiliation(s)
- Yuval Shaked
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 1 Efron St. Bat Galim, Haifa 31096, Israel
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16
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Wetmore C, Daryani VM, Billups CA, Boyett JM, Leary S, Tanos R, Goldsmith KC, Stewart CF, Blaney SM, Gajjar A. Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021. Cancer Med 2016; 5:1416-24. [PMID: 27109549 PMCID: PMC4944867 DOI: 10.1002/cam4.713] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 01/27/2016] [Accepted: 02/28/2016] [Indexed: 01/23/2023] Open
Abstract
Sunitinib malate is a small multi‐targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high‐grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high‐grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression‐free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high‐grade glioma. Most adverse events were of mild‐to‐moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high‐grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.
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Affiliation(s)
- Cynthia Wetmore
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, Georgia, 30322
| | - Vinay M Daryani
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105
| | - Catherine A Billups
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105
| | - James M Boyett
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105
| | - Sarah Leary
- Department of Hematology/Oncology, Seattle Children's Hospital, Seattle, Washington, 98145
| | - Rachel Tanos
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, Georgia, 30322
| | - Kelly C Goldsmith
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, Georgia, 30322
| | - Clinton F Stewart
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105
| | - Susan M Blaney
- Pediatric Oncology, Clinical Care Center, Baylor College of Medicine, Houston, Texas, 77030
| | - Amar Gajjar
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105
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17
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Ronellenfitsch U, Dimitrakopoulou-Strauss A, Jakob J, Kasper B, Nowak K, Pilz LR, Attenberger U, Gaiser T, Egerer G, Fröhling S, Derigs HG, Schwarzbach M, Hohenberger P. Preoperative therapy with pazopanib in high-risk soft tissue sarcoma: a phase II window-of-opportunity study by the German Interdisciplinary Sarcoma Group (GISG-04/NOPASS). BMJ Open 2016; 6:e009558. [PMID: 26739732 PMCID: PMC4716254 DOI: 10.1136/bmjopen-2015-009558] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION For resectable soft tissue sarcoma (STS), radical surgery, usually combined with radiotherapy, is the mainstay of treatment and the only potentially curative modality. Since surgery is often complicated by large tumour size and extensive tumour vasculature, preoperative treatment strategies with the aim of devitalising the tumour are being explored. One option is treatment with antiangiogenic drugs. The multikinase inhibitor pazopanib, which possesses pronounced antiangiogenic effects, has shown activity in metastatic and unresectable STS, but has so far not been tested in the preoperative setting. METHODS AND ANALYSIS This open-label, multicentre phase II window-of-opportunity trial assesses pazopanib as preoperative treatment of resectable STS. Participants receive a 21-day course of pazopanib 800 mg daily during wait time for surgery. Major eligibility criteria are resectable, high-risk adult STS of any location, or metachronous solitary STS metastasis for which resection is planned, and adequate organ function and performance status. The trial uses an exact single-stage design. The primary end point is metabolic response rate (MRR), that is, the proportion of patients with >50% reduction of the mean standardised uptake value (SUVmean) in post-treatment compared to pre-treatment fluorodeoxyglucose positron emission tomography CT. The MRR below which the treatment is considered ineffective is 0.2. The MRR above which the treatment warrants further exploration is 0.4. With a type I error of 5% and a power of 80%, the sample size is 35 evaluable patients, with 12 or more responders as threshold. Main secondary end points are histopathological and MRI response, resectability, toxicity, recurrence-free and overall survival. In a translational substudy, endothelial progenitor cells and vascular epithelial growth factor receptor are analysed as potential prognostic and predictive markers. ETHICS AND DISSEMINATION Approval by the ethics committee II, University of Heidelberg, Germany (2012-019F-MA), German Federal Institute for Drugs and Medical Devices (61-3910-4038155) and German Federal Institute for Radiation Protection (Z5-22463/2-2012-007). TRIAL REGISTRATION NUMBER NCT01543802, EudraCT: 2011-003745-18; Pre-results.
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Affiliation(s)
- Ulrich Ronellenfitsch
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | | | - Jens Jakob
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Bernd Kasper
- Medical Faculty Mannheim, Interdisciplinary Tumor Center, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Kai Nowak
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Lothar R Pilz
- Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ulrike Attenberger
- Medical Faculty Mannheim, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Timo Gaiser
- Medical Faculty Mannheim, Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Gerlinde Egerer
- Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Fröhling
- Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hans-Günter Derigs
- Department of Hematology and Oncology, Klinikum Frankfurt-Höchst, Frankfurt am Main, Germany
| | | | - Peter Hohenberger
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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18
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O'Donnell PH, Karovic S, Karrison TG, Janisch L, Levine MR, Harris PJ, Polite BN, Cohen EEW, Fleming GF, Ratain MJ, Maitland ML. Serum C-Telopeptide Collagen Crosslinks and Plasma Soluble VEGFR2 as Pharmacodynamic Biomarkers in a Trial of Sequentially Administered Sunitinib and Cilengitide. Clin Cancer Res 2015. [PMID: 26199386 DOI: 10.1158/1078-0432.ccr-15-0427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
PURPOSE Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2]. EXPERIMENTAL DESIGN Advanced solid tumor patients received 50 mg sunitinib daily for 14 days. For the next 14 days, patients were randomized to arm A (cilengitide 2,000 mg administered intravenously twice weekly) or arm B (no treatment). The primary endpoint was change in [sVEGFR2] between days 14 and 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin αvβ3, serum c-telopeptide collagen crosslinks (CTx), was also measured. RESULTS Of 21 patients, 14 (7 per arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and SD of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from days 14 to 28 between the arms [arm A: 2.8 ng/mL; 95% confidence interval (CI), 2.1-3.6 vs. arm B: 2.0 ng/mL; 95% CI, 0.72-3.4; P = 0.22, 2-sample t test]. Additional analyses suggested (i) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2] and (ii) sunitinib causes measurable changes in CTx. CONCLUSIONS Cilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination antiangiogenic therapy trials.
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Affiliation(s)
- Peter H O'Donnell
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois
| | - Sanja Karovic
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Theodore G Karrison
- Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois. Department of Health Studies, The University of Chicago, Chicago, Illinois
| | - Linda Janisch
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Matthew R Levine
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Pamela J Harris
- Cancer Therapy Evaluation Program of the National Cancer Institute, Bethesda, Maryland
| | - Blase N Polite
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois
| | - Ezra E W Cohen
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois
| | - Gini F Fleming
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois
| | - Mark J Ratain
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois
| | - Michael L Maitland
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
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19
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Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial. Lung Cancer 2015; 90:288-95. [DOI: 10.1016/j.lungcan.2015.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 09/02/2015] [Accepted: 09/05/2015] [Indexed: 01/10/2023]
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20
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Bouattour M, Payancé A, Wassermann J. Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging. World J Hepatol 2015; 7:2245-2263. [PMID: 26380650 PMCID: PMC4568486 DOI: 10.4254/wjh.v7.i20.2245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/16/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.
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Affiliation(s)
- Mohamed Bouattour
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Audrey Payancé
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Johanna Wassermann
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
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21
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Varkaris A, Corn PG, Parikh NU, Efstathiou E, Song JH, Lee YC, Aparicio A, Hoang AG, Gaur S, Thorpe L, Maity SN, Bar Eli M, Czerniak BA, Shao Y, Alauddin M, Lin SH, Logothetis CJ, Gallick GE. Integrating Murine and Clinical Trials with Cabozantinib to Understand Roles of MET and VEGFR2 as Targets for Growth Inhibition of Prostate Cancer. Clin Cancer Res 2015; 22:107-21. [PMID: 26272062 DOI: 10.1158/1078-0432.ccr-15-0235] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 07/26/2015] [Indexed: 12/29/2022]
Abstract
PURPOSE We performed parallel investigations in cabozantinib-treated patients in a phase II trial and simultaneously in patient-derived xenograft (PDX) models to better understand the roles of MET and VEGFR2 as targets for prostate cancer therapy. EXPERIMENTAL DESIGN In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in tumors from bone biopsies. In mice harboring PDX intrafemurally or subcutaneously, cabozantinib effects on tumor growth, MET, PDX in which MET was silenced, VEGFR2, bone turnover, angiogenesis, and resistance were examined. RESULTS In responsive patients and PDX, islets of viable pMET-positive tumor cells persisted, which rapidly regrew after drug withdrawal. Knockdown of MET in PDX did not affect tumor growth in mice nor did it affect cabozantinib-induced growth inhibition but did lead to induction of FGFR1. Inhibition of VEGFR2 and MET in endothelial cells reduced the vasculature, leading to necrosis. However, each islet of viable cells surrounded a VEGFR2-negative vessel. Reduction of bone turnover was observed in both cohorts. CONCLUSIONS Our studies demonstrate that MET in tumor cells is not a persistent therapeutic target for metastatic castrate-resistant prostate cancer (CRPC), but inhibition of VEGFR2 and MET in endothelial cells and direct effects on osteoblasts are responsible for cabozantinib-induced tumor inhibition. However, vascular heterogeneity represents one source of primary therapy resistance, whereas induction of FGFR1 in tumor cells suggests a potential mechanism of acquired resistance. Thus, integrated cross-species investigations demonstrate the power of combining preclinical models with clinical trials to understand mechanisms of activity and resistance of investigational agents.
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Affiliation(s)
- Andreas Varkaris
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paul G Corn
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nila U Parikh
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eleni Efstathiou
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jian H Song
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yu-Chen Lee
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ana Aparicio
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anh G Hoang
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sanchaika Gaur
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Programs in Cancer Biology and Cancer Metastasis, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas
| | - Lynnelle Thorpe
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Programs in Cancer Biology and Cancer Metastasis, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas
| | - Sankar N Maity
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Menashe Bar Eli
- Programs in Cancer Biology and Cancer Metastasis, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bogdan A Czerniak
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yiping Shao
- Department of Imaging Physics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mian Alauddin
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sue-Hwa Lin
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher J Logothetis
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gary E Gallick
- Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas. Programs in Cancer Biology and Cancer Metastasis, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
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Ch'ang HJ. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma. World J Hepatol 2015; 7:2029-40. [PMID: 26261692 PMCID: PMC4528276 DOI: 10.4254/wjh.v7.i16.2029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 07/21/2015] [Accepted: 07/24/2015] [Indexed: 02/06/2023] Open
Abstract
The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma (HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide.
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Affiliation(s)
- Hui-Ju Ch'ang
- Hui-Ju Ch'ang, National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan
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23
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Predictive and prognostic significance of circulating endothelial cells in advanced non-small cell lung cancer patients. Tumour Biol 2015; 36:9031-7. [DOI: 10.1007/s13277-015-3657-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 06/09/2015] [Indexed: 12/31/2022] Open
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Flaherty KT, Manola JB, Pins M, McDermott DF, Atkins MB, Dutcher JJ, George DJ, Margolin KA, DiPaola RS. BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol 2015; 33:2384-91. [PMID: 26077237 DOI: 10.1200/jco.2015.60.9727] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
PURPOSE On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade. PATIENTS AND METHODS A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point. RESULTS Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms. CONCLUSION The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy.
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Affiliation(s)
- Keith T Flaherty
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
| | - Judith B Manola
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - Michael Pins
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - David F McDermott
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - Michael B Atkins
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - Janice J Dutcher
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - Daniel J George
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - Kim A Margolin
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
| | - Robert S DiPaola
- Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ
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Addison CL, Pond GR, Cochrane B, Zhao H, Chia SK, Levine MN, Clemons M. Correlation of baseline biomarkers with clinical outcomes and response to fulvestrant with vandetanib or placebo in patients with bone predominant metastatic breast cancer: An OCOG ZAMBONEY sub-study. J Bone Oncol 2015; 4:47-53. [PMID: 26579488 PMCID: PMC4620970 DOI: 10.1016/j.jbo.2015.04.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 04/16/2015] [Accepted: 04/17/2015] [Indexed: 12/14/2022] Open
Abstract
Background Bone metastases are common in women with breast cancer and often result in skeletal related events (SREs). As the angiogenic factor vascular endothelial growth factor (VEGF) regulates osteoclast activity and is associated with more extensive bone metastases and SRE risk in metastatic breast cancer, we hypothesized that blockade of VEGF signaling could be a therapeutic strategy for inhibiting bone metastases progression and possibly prolonging overall (OS) or progression-free survival (PFS). The Zamboney trial was a randomized placebo-controlled study designed to assess whether patients with bone predominant metastatic breast cancer benefited from addition of the VEGF receptor (VEGFR) targeting agent, vandetanib, to endocrine therapy with fulvestrant. As a companion study, evaluation of biomarkers and their potential association with response to vandetanib or SRE risk was performed. Methods Baseline overnight fasted serum from enrolled patients was analyzed for levels of various putative biomarkers including; VEGF-A, soluble (s)VEGFR2, sVEGFR3, transforming growth factor (TGF)-β1 and activinA by ELISA. Spearman correlation coefficients and Wilcoxon rank sum tests were used to investigate potential relationships between biomarker values and baseline clinical parameters. Prognostic and predictive ability of each marker was investigated using Cox proportional hazards regression with adjustments for treatment and baseline strata of serum CTx (<400 versus ≥400 ng/L). Results Of 129 enrolled patients, serum was available for analysis in 101; 51 in vandetanib and 50 in placebo arm. Mean age amongst consenting patients was 59.8 years. Clinical characteristics were not significantly different between patients with or without serum biomarker data and serum markers were similar for patients by treatment arm. Baseline sVEGFR2 was prognostic for OS (HR=0.77, 95% CI=0.61–0.96, p=0.020), and although a modest association was observed, it was not significant for PFS (HR=0.90, 95% CI=0.80–1.01, p=0.085) nor time to first SRE (HR=0.82, 95% CI=0.66–1.02, p=0.079). When interaction terms were evaluated, sVEGFR2 was not found to be predictive of response to vandetanib, although a modest association remained with respect to PFS (interaction p=0.085). No other marker showed any significant prognostic or predictive ability with any measured outcome. Conclusions In this clinical trial, sVEGFR2 appeared prognostic for OS, hence validation of sVEGFR2 should be conducted. Moreover, the role of sVEGFR2 in breast cancer bone metastasis progression should be elucidated.
Baseline VEGF, sVEGFR3, TGF-β or activinA were not associated with clinical outcomes in patients treated with fulvestrant in conjunction with vandetanib or placebo. Baseline sVEGFR2 was modestly associated with clinical outcomes including PFS, OS and time to first skeletal event. Increased baseline sVEGFR2 was associated with improved clinical outcomes in this study sample. These findings support the need for future studies of the role of sVEGFR2 in bone metastasis progression.
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Key Words
- BP, bisphosphonate
- BPI, brief pain inventory
- Biomarker
- Bone metastasis
- Breast cancer
- CTx, C-telopeptide
- ER, estrogen receptor
- FACT-BP, Functional assessment of cancer therapy-bone pain
- OS, overall survival
- PFS, progression free survival
- PR, progesterone receptor
- Patient outcome
- RANKL, Receptor Activator NF-KB ligand
- SRE, skeletal related event
- Skeletal related event
- TGF-β, transforming growth factor beta
- VEGF, vascular endothelial growth factor
- Vandetanib
- sVEGFR, soluble vascular endothelial growth factor receptor
- uNTx, urinary N-telopeptide
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Affiliation(s)
- Christina L Addison
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Box 926, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 ; Department of Medicine, University of Ottawa, Ottawa, ON, Canada ; Department of Biochemistry, Microbiology and Immunology University of Ottawa, Ottawa, ON, Canada
| | - Gregory R Pond
- McMaster University and Ontario Clinical Oncology Group, Hamilton, ON, Canada
| | - Brandy Cochrane
- McMaster University and Ontario Clinical Oncology Group, Hamilton, ON, Canada
| | - Huijun Zhao
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Box 926, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6
| | | | - Mark N Levine
- McMaster University and Ontario Clinical Oncology Group, Hamilton, ON, Canada
| | - Mark Clemons
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Box 926, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 ; Department of Medicine, University of Ottawa, Ottawa, ON, Canada
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Zhu JQ, Ou WB. Therapeutic targets in gastrointestinal stromal tumors. World J Transl Med 2015; 4:25-37. [DOI: 10.5528/wjtm.v4.i1.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 09/14/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The tumorigenesis of GISTs is driven by gain-of-function mutations in KIT or platelet-derived growth factor receptor α (PDGFRA), resulting in constitutive activation of the tyrosine kinase and its downstream signaling pathways. Oncogenic KIT or PDGFRA mutations are compelling therapeutic targets for the treatment of GISTs, and the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GISTs. However, most GIST patients develop clinical resistance to imatinib and other tyrosine kinase inhibitors. Five mechanisms of resistance have been characterized: (1) acquisition of a secondary point mutation in KIT or PDGFRA; (2) genomic amplification of KIT; (3) activation of an alternative receptor tyrosine kinase; (4) loss of KIT oncoprotein expression; and (5) wild-type GIST. Currently, sunitinib is used as a second-line treatment for patients after imatinib failure, and regorafenib has been approved for patients whose disease is progressing on both imatinib and sunitinib. Phase II/III trials are currently in progress to evaluate novel inhibitors and immunotherapies targeting KIT, its downstream effectors such as phosphatidylinositol 3-kinase, protein kinase B and mammalian target of rapamycin, heat shock protein 90, and histone deacetylase inhibitor. Other candidate targets have been identified, including ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A. These candidates warrant clinical evaluation as novel therapeutic targets in GIST.
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Zurita AJ, Khajavi M, Wu HK, Tye L, Huang X, Kulke MH, Lenz HJ, Meropol NJ, Carley W, DePrimo SE, Lin E, Wang X, Harmon CS, Heymach JV. Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours. Br J Cancer 2015; 112:1199-205. [PMID: 25756398 PMCID: PMC4385961 DOI: 10.1038/bjc.2015.73] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 12/23/2014] [Accepted: 01/29/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study. METHODS Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed. RESULTS Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4. CONCLUSIONS Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.
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Affiliation(s)
- A J Zurita
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA
| | - M Khajavi
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA
| | - H-K Wu
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA
| | - L Tye
- Pfizer Inc., La Jolla, CA, USA
| | - X Huang
- Pfizer Inc., La Jolla, CA, USA
| | - M H Kulke
- Dana-Farber Cancer Institute, Boston, MA, USA
| | - H-J Lenz
- USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - N J Meropol
- University Hospitals Case Medical Center Seidman Cancer Center, Case Comprehensive Cancer Center and Case Western Reserve University, Cleveland, OH, USA
| | | | | | - E Lin
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA
| | - X Wang
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA
| | | | - J V Heymach
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA
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Hayashi H, Arao T, Matsumoto K, Kimura H, Togashi Y, Hirashima Y, Horita Y, Iwasa S, Okita NT, Honma Y, Takashima A, Kato K, Hamaguchi T, Shimada Y, Nakagawa K, Nishio K, Yamada Y. Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma. Oncotarget 2015; 5:2588-95. [PMID: 24809949 PMCID: PMC4058029 DOI: 10.18632/oncotarget.1811] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.
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Affiliation(s)
- Hidetoshi Hayashi
- Department of Genome Biology, Kinki University Faculty of Medicine, Osakasayama City, Osaka, Japan
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Katz OB, Shaked Y. Host effects contributing to cancer therapy resistance. Drug Resist Updat 2014; 19:33-42. [PMID: 25575621 DOI: 10.1016/j.drup.2014.12.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 12/08/2014] [Accepted: 12/17/2014] [Indexed: 01/14/2023]
Abstract
There are several approaches for the management of malignant disease. However, tumor resistance to therapy is still a major challenge in the clinic. Efflux transporters, genetic responses and enzyme activity in tumor cells are examples of the main modalities that account for resistance to therapy. In addition, emerging evidence suggests that the host also plays a significant role in promoting therapy resistance. Recruitment of different host cell types to the treated tumor site occurs in response to a range of therapies, including chemotherapy, radiation and even targeted drugs. This host response may have a protective effect on the tumor cells, not only negating anti-tumor activity, but also promoting a resistant tumor. In this review, we focus on host-tumor interactions leading to therapy resistance with special emphasis on different host cells and secreted factors within the tumor microenvironment. The development of novel inhibitors that block the host response to therapy could be used as a treatment strategy to enhance therapy outcomes and survival.
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Affiliation(s)
- Ofrat Beyar Katz
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Yuval Shaked
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
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Manzoni M, Comolli G, Torchio M, Mazzini G, Danova M. Circulating endothelial cells and their subpopulations: role as predictive biomarkers in antiangiogenic therapy for colorectal cancer. Clin Colorectal Cancer 2014; 14:11-7. [PMID: 25591800 DOI: 10.1016/j.clcc.2014.12.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 12/13/2014] [Accepted: 12/16/2014] [Indexed: 12/13/2022]
Abstract
Several anticancer therapies have been developed to block angiogenesis, a key mechanism in tumor growth and metastasis. The predominantly cytostatic action of these compounds makes an assessment of their clinical activities inadequate if based only on the reduction of the tumor dimensions, as this may not reflect their true biologic efficacy. Thus, it is crucial to identify biomarkers that permit the recognition of potentially responsive subjects and to spare toxicity in those who are unlikely to benefit from treatment. Circulating endothelial cells (CECs) have been recently indicated as potential surrogate biomarkers of angiogenesis in several types of cancer. The possibility of rapidly quantifying these cells represents a promising tool for monitoring the clinical outcome of tumors with the potential to assess response to various treatments. However, the identification and quantification of CECs is technically difficult and not well standardized. A variety of methods to detect CECs in patients with solid tumors have been used; these are based on different technical approaches, combinations of surface markers, sample handling, and staining protocols. With an expanding interest in the field of potential clinical applications for CECs in oncology, the development of standardized protocols for analysis is mandatory. The aim of this review was to critically summarize the available data concerning the clinical value of CECs and their subpopulations as biomarkers of antiangiogenic therapy in patients with metastatic colorectal cancer.
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Affiliation(s)
- Mariangela Manzoni
- Department of Medical Oncology, Azienda Ospedaliera "Ospedale Maggiore", Crema, Italy.
| | - Giuditta Comolli
- Laboratories of Biotechnology and Virology/Microbiology Department, Fondazione IRCCS, Pavia, Italy
| | - Martina Torchio
- Institute of Molecular Genetics, National Research Council, Pavia, Italy
| | - Giuliano Mazzini
- Department of Internal Medicine and Medical Oncology, Ospedale di Vigevano, Vigevano, Italy
| | - Marco Danova
- Institute of Molecular Genetics, National Research Council, Pavia, Italy
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Schier R, El-Zein R, Cortes A, Liu M, Collins M, Rafat N, Teschendorf P, Wu HK, Heymach J, Mehran R, Riedel B. Endothelial progenitor cell mobilization by preoperative exercise: a bone marrow response associated with postoperative outcome. Br J Anaesth 2014; 113:652-60. [PMID: 24880828 DOI: 10.1093/bja/aeu135] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Preoperative anaemia is associated with increased morbidity in patients undergoing major surgery. Whether erythrocytes are the only bone-marrow-derived cell lineage that associates with increased surgical complications is unknown. This prospective observational trial studied the mobilization of endothelial progenitor cells (EPCs) in response to exercise in association with postoperative complications. METHODS After IRB approval, 60 subjects undergoing major thoracic surgery were exercised to exhaustion (peak V̇(O₂)). Peripheral blood collected before and after peak exercise was quantified for EPC lineages by fluorescence-activated cell sorter analysis. Complication analysis was based on the Clavien-Dindo classification. RESULTS Exhaustive exercise increased EPC [CD45-133+34+ cells=150 (0.00-5230) to 220 (0.00-1270) cells μl(-1); median change (range)=20 (-4,180-860) cells μl(-1); P=0.03] but not mature endothelial cell (EC) subpopulations. Pre-exercise levels [odds ratio (OR)=0.86, 95% confidence interval (CI): 0.37-2.00, P=0.72), change after exercise as a continuous variable (OR=0.95, 95% CI: 0.41-2.22, P=0.91) and a positive response after exercise (change >0 cells μl(-1); OR=0.41, 95% CI: 0.13-1.28, P=0.12) were not statistically significantly associated with the incidence of postoperative complications. Post-hoc receiver operating characteristic curve analyses revealed that subjects with a CD45-133+34+ increase ≥60 cells μl(-1) in response to exercise suffered fewer postoperative complications [86% sensitivity, 48% specificity and AUC=0.67 (95% CI: 0.52-0.81)]. CONCLUSIONS Preoperative exercise induces EPC into the peripheral circulation. Subjects with a poor EPC response had a pre-existing propensity for postoperative complications. This warrants further research into the role of bone marrow function as a critical component to endothelial repair mechanisms. CLINICAL TRIAL REGISTRATION IRB 2003-0434 (University of Texas M.D. Anderson Cancer Center, Houston, TX, USA).
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Affiliation(s)
- R Schier
- Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany
| | | | | | - M Liu
- Department of Epidemiology
| | - M Collins
- Centre for Biostatistics and Clinical Trials and
| | - N Rafat
- Department of Pediatrics I, University Children's Heidelberg, Heidelberg, Germany
| | - P Teschendorf
- Department of Anaesthesiology and Intensive Care Medicine, Hospital of Osnabrueck, Osnabrueck, Germany
| | - Hua-Kang Wu
- Department of Thoracic/Head and Neck Oncology, and
| | - J Heymach
- Department of Thoracic/Head and Neck Oncology, and
| | - R Mehran
- Department of Thoracic Surgery, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
| | - B Riedel
- Department of Cancer Anaesthetics and Pain Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia
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Judson I, Scurr M, Gardner K, Barquin E, Marotti M, Collins B, Young H, Jürgensmeier JM, Leahy M. Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma. Clin Cancer Res 2014; 20:3603-12. [PMID: 24714778 DOI: 10.1158/1078-0432.ccr-13-1881] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Cediranib is a potent VEGF signaling inhibitor with activity against all three VEGF receptors and KIT. This phase II study evaluated the antitumor activity of cediranib in patients with metastatic gastrointestinal stromal tumor (GIST) resistant/intolerant to imatinib, or metastatic soft-tissue sarcomas (STS; ClinicalTrials.gov, NCT00385203). EXPERIMENTAL DESIGN Patients received cediranib 45 mg/day. Primary objective was to determine the antitumor activity of cediranib according to changes in 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG-PET) tumor uptake in patients with GIST using maximum standardized uptake values (SUVmax). Secondary objectives included objective tumor response and tolerability in patients with GIST/STS. RESULTS Thirty-four of 36 enrolled patients were treated (GIST n = 24; STS n = 10). At day 29, five patients had confirmed decreases in SUVmax (≥10% from day 8) and two had confirmed partial metabolic responses (≥25% decrease), but arithmetic mean percentage changes in SUVmax, averaged across the cohort, were not significant at day 8 [6.8%; 95% confidence interval (CI), 19.95-33.54) or day 29 (4.6%; 95% CI, 8.05-17.34). Eleven patients with GIST achieved a best objective tumor response of stable disease; eight achieved stable disease ≥16 weeks. In patients with STS, four of six with alveolar soft-part sarcoma (ASPS) achieved confirmed and durable partial responses. The commonest adverse events were diarrhea (85%), fatigue (74%), and hypertension (68%). CONCLUSIONS In patients progressing on imatinib/sunitinib, cediranib 45 mg/day demonstrated evidence of activity by (18)FDG-PET, but did not reduce average SUVmax. Evidence of antitumor activity was seen in ASPS.
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Affiliation(s)
- Ian Judson
- Authors' Affiliations: Royal Marsden Hospital, London;
| | | | - Kate Gardner
- Authors' Affiliations: Royal Marsden Hospital, London
| | | | | | | | | | | | - Michael Leahy
- Christie Hospital NHS Foundation Trust, Manchester, United Kingdom
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Byers LA. Molecular Profiling. Lung Cancer 2014. [DOI: 10.1002/9781118468791.ch3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Heymach JV, Cascone T. Tumor Microenvironment, Angiogenesis Biology, and Targeted Therapy. Lung Cancer 2014. [DOI: 10.1002/9781118468791.ch33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Mehran R, Nilsson M, Khajavi M, Du Z, Cascone T, Wu HK, Cortes A, Xu L, Zurita A, Schier R, Riedel B, El-Zein R, Heymach JV. Tumor endothelial markers define novel subsets of cancer-specific circulating endothelial cells associated with antitumor efficacy. Cancer Res 2014; 74:2731-41. [PMID: 24626092 DOI: 10.1158/0008-5472.can-13-2044] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Circulating endothelial cells (CEC) are derived from multiple sources, including bone marrow (circulating endothelial progenitors; CEP), and established vasculature (mature CEC). Although CECs have shown promise as a biomarker for patients with cancer, their utility has been limited, in part, by the lack of specificity for tumor vasculature and the different nonmalignant causes that can impact CEC. Tumor endothelial markers (TEM) are antigens enriched in tumor versus nonmalignant endothelia. We hypothesized that TEMs may be detectable on CEC and that these circulating TEM(+) endothelial cells (CTEC) may be a more specific marker for cancer and tumor response than standard CEC. We found that tumor-bearing mice had a relative increase in numbers of circulating CTEC, specifically with increased levels of TEM7 and TEM8 expression. Following treatment with various vascular-targeting agents, we observed a decrease in CTEC that correlated with the reductions in tumor growth. We extended these findings to human clinical samples and observed that CTECs were present in patients with esophageal cancer and non-small cell lung cancer (N = 40), and their levels decreased after surgical resection. These results demonstrate that CTECs are detectable in preclinical cancer models and patients with cancer. Furthermore, they suggest that CTECs offer a novel cancer-associated marker that may be useful as a blood-based surrogate for assessing the presence of tumor vasculature and antiangiogenic drug activity.
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Affiliation(s)
- Reza Mehran
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Monique Nilsson
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Mehrdad Khajavi
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Zhiqiang Du
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Tina Cascone
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Hua Kang Wu
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Andrea Cortes
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Li Xu
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Amado Zurita
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Robert Schier
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Bernhard Riedel
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - Randa El-Zein
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
| | - John V Heymach
- Authors' Affiliations: Departments of Thoracic and Cardiovascular Surgery,Thoracic/Head and Neck Medical Oncology, Epidemiology, Genitourinary Medical Oncology, and The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany; and Department of Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria, Australia
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Yu HK, Kim SJ, Kim JS. About CD45-/CD31+/CD105+ circulating cells in patients with gynecologic malignancies--response. Clin Cancer Res 2014; 20:1394-5. [PMID: 24590887 DOI: 10.1158/1078-0432.ccr-13-3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Hyun-Kyung Yu
- Authors' Affiliations: Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin; Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; and Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Bertolini F, Mancuso P, Heymach JV. About CD45-/CD31+/CD105+ circulating cells in patients with gynecologic malignancies--letter. Clin Cancer Res 2014; 20:1393. [PMID: 24590886 DOI: 10.1158/1078-0432.ccr-13-2855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Francesco Bertolini
- Authors' Affiliations: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy; and The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Versleijen-Jonkers YMH, Vlenterie M, van de Luijtgaarden ACM, van der Graaf WTA. Anti-angiogenic therapy, a new player in the field of sarcoma treatment. Crit Rev Oncol Hematol 2014; 91:172-85. [PMID: 24613529 DOI: 10.1016/j.critrevonc.2014.02.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 12/19/2013] [Accepted: 02/05/2014] [Indexed: 01/12/2023] Open
Abstract
Sarcomas encompass a heterogeneous family of mesenchymal malignancies. In metastatic disease improvement in outcome has been limited and there is a clear need for the development of new therapies. One potential target is angiogenesis, already an accepted target for treatment of more prevalent cancers. Multiple (pre)clinical studies focused on the role of angiogenesis and anti-angiogenic treatment in sarcomas. However, getting significant results is complicated due to the relatively small number of patients and the broad range of sarcoma subtypes. Recently, pazopanib has been approved for the treatment of advanced soft tissue sarcoma patients, which is an important step forward and paves the way for the introduction of anti-angiogenic treatment in sarcomas. However, more studies are needed to understand the biological mechanisms by which patients respond to angiogenic inhibitors and to detect markers of response. This review covers the knowledge that has been gained on the role of angiogenesis and anti-angiogenic therapy in sarcomas.
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Affiliation(s)
- Yvonne M H Versleijen-Jonkers
- Department of Medical Oncology, Radboud University Medical Center, Internal Postal Code 452, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Myrella Vlenterie
- Department of Medical Oncology, Radboud University Medical Center, Internal Postal Code 452, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Addy C M van de Luijtgaarden
- Department of Medical Oncology, Radboud University Medical Center, Internal Postal Code 452, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Winette T A van der Graaf
- Department of Medical Oncology, Radboud University Medical Center, Internal Postal Code 452, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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Hansson EK, Amantea MA, Westwood P, Milligan PA, Houk BE, French J, Karlsson MO, Friberg LE. PKPD Modeling of VEGF, sVEGFR-2, sVEGFR-3, and sKIT as Predictors of Tumor Dynamics and Overall Survival Following Sunitinib Treatment in GIST. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2013; 2:e84. [PMID: 24257372 PMCID: PMC3852160 DOI: 10.1038/psp.2013.61] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 10/06/2013] [Indexed: 01/26/2023]
Abstract
The predictive value of longitudinal biomarker data (vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, and soluble stem cell factor receptor (sKIT)) for tumor response and survival was assessed based on data from 303 patients with imatinib-resistant gastrointestinal stromal tumors (GIST) receiving sunitinib and/or placebo treatment. The longitudinal tumor size data were well characterized by a tumor growth inhibition model, which included, as significant descriptors of tumor size change, the model-predicted relative changes from baseline over time for sKIT (most significant) and sVEGFR-3, in addition to sunitinib exposure. Survival time was best described by a parametric time-to-event model with baseline tumor size and relative change in sVEGFR-3 over time as predictive factors. Based on the proposed modeling framework to link longitudinal biomarker data with overall survival using pharmacokinetic-pharmacodynamic models, sVEGFR-3 demonstrated the greatest predictive potential for overall survival following sunitinib treatment in GIST.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e84; doi:10.1038/psp.2013.61; advance online publication 20 November 2013.
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Affiliation(s)
- E K Hansson
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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40
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Grivas PD, Daignault S, Tagawa ST, Nanus DM, Stadler WM, Dreicer R, Kohli M, Petrylak DP, Vaughn DJ, Bylow KA, Wong SG, Sottnik JL, Keller ET, Al-Hawary M, Smith DC, Hussain M. Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer 2013; 120:692-701. [DOI: 10.1002/cncr.28477] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 09/30/2013] [Accepted: 10/04/2013] [Indexed: 01/05/2023]
Affiliation(s)
- Petros D. Grivas
- Department of Internal Medicine; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan
| | - Stephanie Daignault
- Biostatistics Department; University of Michigan Comprehensive Cancer Center; Ann Arbor, Michigan
| | - Scott T. Tagawa
- Departments of Medicine and Urology; Weill Cornell Medical College; New York
| | - David M. Nanus
- Departments of Medicine and Urology; Weill Cornell Medical College; New York
| | | | - Robert Dreicer
- Department of Solid Tumor Oncology; Cleveland Clinic; Cleveland Ohio
| | - Manish Kohli
- Department of Oncology; Mayo Clinic; Rochester Minnesota
| | - Daniel P. Petrylak
- Departments of Medical Oncology and Urology; Yale University Cancer Center; New Haven Connecticut
| | - David J. Vaughn
- Department of Medicine; University of Pennsylvania Abramson Cancer Center; Philadelphia Pennsylvania
| | - Kathryn A. Bylow
- Department of Medicine; Medical College of Wisconsin; Milwaukee Wisconsin
| | - Steven G. Wong
- Department of Medicine; University of California at Los Angeles School of Medicine; Los Angeles California
| | - Joseph L. Sottnik
- Department of Urology; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan
| | - Evan T. Keller
- Departments of Urology and Pathology; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan
| | - Mahmoud Al-Hawary
- Department of Radiology; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan
| | - David C. Smith
- Department of Internal Medicine; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan
| | - Maha Hussain
- Department of Internal Medicine; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan
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Yu HK, Lee HJ, Choi HN, Ahn JH, Choi JY, Song HS, Lee KH, Yoon Y, Yi LSH, Kim JS, Kim SJ, Kim TJ. Characterization of CD45-/CD31+/CD105+ circulating cells in the peripheral blood of patients with gynecologic malignancies. Clin Cancer Res 2013; 19:5340-50. [PMID: 23922300 DOI: 10.1158/1078-0432.ccr-12-3685] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Circulating endothelial cells (CEC) have been widely used as a prognostic biomarker and regarded as a promising strategy for monitoring the response to treatment in several cancers. However, the presence and biologic roles of CECs have remained controversial for decades because technical standards for the identification and quantification of CECs have not been established. Here, we hypothesized that CECs detected by flow cytometry might be monocytes rather than endothelial cells. EXPERIMENTAL DESIGN The frequency of representative CEC subsets (i.e., CD45(-)/CD31(+), CD45(-)/CD31(+)/CD146(+), CD45(-)/CD31(+)/CD105(+)) was analyzed in the peripheral blood of patients with gynecologic cancer (n = 56) and healthy volunteers (n = 44). CD45(-)/CD31(+) cells, which are components of CECs, were isolated and the expression of various markers (CD146, CD105, vWF, and CD144 for endothelial cells; CD68 and CD14 for monocytes) was examined by immunocytochemistry. RESULTS CD45(-)/CD31(+)/CD105(+) cells were significantly increased in the peripheral blood of patients with cancer, whereas evaluation of CD45(-)/CD31(+)/CD146(+) cells was not possible both in patients with cancer and healthy controls due to the limited resolution of the flow cytometry. Immunocytochemistry analyses showed that these CD45(-)/CD31(+)/CD105(+) cells did not express vWF and CD146 but rather CD144. Furthermore, CD45(-)/CD31(+)/CD105(+) cells uniformly expressed the monocyte-specific markers CD14 and CD68. These results suggest that CD45(-)/CD31(+)/CD105(+) cells carry the characteristics of monocytes rather than endothelial cells. CONCLUSIONS Our data indicate that CD45(-)/CD31(+)/CD105(+) circulating cells, which are significantly increased in the peripheral blood of patients with gynecologic cancer, are monocytes rather than endothelial cells. Further investigation is required to determine the biologic significance of their presence and function in relation with angiogenesis.
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Affiliation(s)
- Hyun-Kyung Yu
- Authors' Affiliations: Mogam Biotechnology Research Institute, Yongin; Department of Biological Science, Sungkyunkwan University, Suwon; Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul; Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; and Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Rajendra R, Pollack SM, Jones RL. Management of gastrointestinal stromal tumors. Future Oncol 2013; 9:193-206. [PMID: 23414470 DOI: 10.2217/fon.12.178] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) comprise <1% of all gastrointestinal tumors, but are the most common mesenchymal tumors of the GI tract. This review highlights the dramatic changes in clinical practice with regards to GIST in the last decade, with a focus on overall management and recent developments. For localized primary GISTs, surgical resection is the mainstay of therapy with the 5-year survival rate after complete resection averaging approximately 50-65%. Factors such as tumor size, mitotic rate, tumor location, kinase mutational status and occurrence of tumor rupture have been extensively studied and proposed to be predictors of outcome. Adjuvant imatinib is proposed as an option for those patients with a substantial risk of relapse. Unresectable metastatic or recurrent GIST can be treated with imatinib, with a remarkable response rate (50-70%) and prolonged survival (median progression-free survival: 18-20 months; median overall survival: 51-57 months). Sunitinib is licensed as a second-line therapy following progression on imatinib. Other promising systemic therapies include regorafenib and agents targeting the PI3K/mTOR pathway.
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Affiliation(s)
- Rajeev Rajendra
- University of Washington/Fred Hutchinson Cancer Research Center, 825 Eastlake Avenue E., G3630, Seattle, WA 98109-1023, USA
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Morotti M, Becker CM, Menada MV, Ferrero S. Targeting tyrosine-kinases in ovarian cancer. Expert Opin Investig Drugs 2013; 22:1265-79. [PMID: 23815710 DOI: 10.1517/13543784.2013.816282] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Epithelial ovarian cancer (EOC) is the leading cause of gynaecologic cancer death. Although in some cases initial treatment is effective, most of the women diagnosed with EOC will probably need medical treatment for their disease. There is a critical need to develop effective new strategies for the management of patients with advanced or recurrent EOC, and targeted therapy with tyrosine kinase inhibitors (TKIs) has continued to be an area of active research and development in this setting. AREAS COVERED This review summarises the available evidence on the use of TKIs in the clinical management of women with EOC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches up to March 2013. EXPERT OPINION Several Phase I/II and III trials evaluated TKIs in EOC; however, it is difficult to draw conclusions on the efficacy of TKI regimens in these patients. TKIs seem to be better tolerated than conventional chemotherapy with a different toxicity profile. A better understanding of the signalling pathways, the toxicity profiles, the potential pharmacokinetic interactions as well as the identification of predictive biomarkers are needed to better identify a targeted patient population before these agents become part of routine treatment.
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Affiliation(s)
- Matteo Morotti
- University of Genoa, San Martino Hospital, Department of Obstetrics and Gynaecology , Largo R. Benzi 1, 16132 Genoa , Italy +01139010511525 ; +01139010511525 ;
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Fahey CE, Milner RJ, Kow K, Bacon NJ, Salute ME. Apoptotic effects of the tyrosine kinase inhibitor, masitinib mesylate, on canine osteosarcoma cells. Anticancer Drugs 2013; 24:519-26. [DOI: 10.1097/cad.0b013e32836002ba] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies. Oncogene 2013; 33:1341-7. [PMID: 23524584 DOI: 10.1038/onc.2013.94] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Revised: 02/03/2013] [Accepted: 02/03/2013] [Indexed: 12/22/2022]
Abstract
In addition to its direct effects on tumor cells, chemotherapy can rapidly activate various host processes that contribute to therapy resistance and tumor regrowth. The host response to chemotherapy consists of changes in numerous cell types and cytokines. Examples include the acute mobilization and tumor homing of pro-angiogenic bone marrow-derived cells, activation of cells in the tumor microenvironment to produce systemic or paracrine factors, and tissue-specific responses that provide a protective niche for tumor cells. All of these factors reduce chemotherapy efficacy, and blocking the host response at various levels may therefore significantly improve treatment outcome. However, before the combination of conventional chemotherapy with agents blocking specific aspects of the host response can be implemented into clinical practice, a better understanding of the molecular mechanisms behind the host response is required.
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Villaflor VM, Salgia R. Targeted agents in non-small cell lung cancer therapy: What is there on the horizon? J Carcinog 2013; 12:7. [PMID: 23599689 PMCID: PMC3622362 DOI: 10.4103/1477-3163.109253] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 01/10/2013] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is a heterogeneous group of diseases. There has been much research in lung cancer over the past decade which has advanced our ability to treat these patients with a more personalized approach. The scope of this paper is to review the literature and give a broad understanding of the current molecular targets for which we currently have therapies as well as other targets for which we may soon have therapies. Additionally, we will cover some of the issues of resistance with these targeted therapies. The molecular targets we intend to discuss are epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), anaplastic large-cell lymphoma kinase (ALK), KRAS, C-MET/RON, PIK3CA. ROS-1, RET Fibroblast growth factor receptor (FGFR). Ephrins and their receptors, BRAF, and immunotherapies/vaccines. This manuscript only summarizes the work which has been done to date and in no way is meant to be comprehensive.
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Affiliation(s)
- Victoria M Villaflor
- Department of Medicine, Section of Hematology/Oncology University of Chicago, Chicago, IL, 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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Giuliano S, Pagès G. Mechanisms of resistance to anti-angiogenesis therapies. Biochimie 2013; 95:1110-9. [PMID: 23507428 DOI: 10.1016/j.biochi.2013.03.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 03/04/2013] [Indexed: 12/19/2022]
Abstract
Angiogenesis, the formation of new blood vessels from preexisting ones, provides oxygen and nutrients to actively proliferating tumor cells. Hence, it represents a critical aspect of tumor progression and metastasis. Because inhibition of angiogenesis represents a major approach to cancer treatment, the development of inhibitors of angiogenesis is a major challenge. The first FDA approved anti-angiogenic drug bevacizumab, a humanized monoclonal antibody directed against the Vascular Endothelial Growth Factor (VEGF), has been approved for the treatment of metastatic colorectal, lung, breast, and kidney cancers. The encouraging results have lead to the development, in the past few years, of other agents targeting angiogenic pathways as potent anti-cancer drugs and a number of them have been approved for metastatic breast, lung, kidney, and central nervous system cancers. Despite a statistically significant increase in progression free survival, which has accelerated FDA approval, no major benefit to overall survival was described and patients inevitably relapsed due to acquired resistance. However, while progression free survival was increased by only a few months for the majority of the patients, some clearly benefited from the treatment with a real increase in life span. The objective of this review is to present an overview of the different treatments targeting angiogenesis, their efficacy and the mechanisms of resistance that have been identified in different cancer types. It is essential to understand how resistance (primary or acquired over time) develops and how it may be overcome.
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Affiliation(s)
- Sandy Giuliano
- University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice (IRCAN) CNRS Unit 7284/INSERM Unit 1081, 33 Avenue de Valombrose, 06189 Nice, France
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Somlo G, Atzori F, Strauss LC, Geese WJ, Specht JM, Gradishar WJ, Rybicki A, Sy O, Vahdat LT, Cortes J. Dasatinib plus capecitabine for advanced breast cancer: safety and efficacy in phase I study CA180004. Clin Cancer Res 2013; 19:1884-93. [PMID: 23403636 DOI: 10.1158/1078-0432.ccr-12-0652] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
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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Affiliation(s)
- George Somlo
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
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Wang J, Xiao J, Wei X, Wang L, Lin L, Liu Z, Wang X, Sun B, Li K. Circulating endothelial cells and tumor blood volume as predictors in lung cancer. Cancer Sci 2013; 104:445-52. [PMID: 23298271 DOI: 10.1111/cas.12097] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 12/13/2012] [Accepted: 12/18/2012] [Indexed: 12/19/2022] Open
Abstract
The current criteria for evaluating antiangiogenic efficacy is insufficient as tumor shrinkage occurs after blood perfusion decreases. Tumor blood volume (BV) in computed tomography perfusion imaging and circulating endothelial cells (CEC) might predict the status of angiogenesis. The present study aimed to validate their representation as feasible predictors in non-small-cell lung carcinoma (NSCLC). A total of 74 patients was categorized randomly into two arms undergoing regimens of vinorelbine and cisplatin (Navelbine and platinum [NP]) with rh-endostatin or single NP. The response rate, perfusion imaging indexes and activated CEC (aCEC) during treatment were recorded. Progression-free survival (PFS) was determined through follow up. Correlations among the above indicators, response and PFS were analyzed: aCEC increased significantly in cases of progressive disease after single NP chemotherapy (P = 0.024). Tumor BV decreased significantly in cases with a clinical benefit in the combined arm (P = 0.026), whereas inverse correlations existed between ∆aCEC (post-therapeutic value minus the pre-therapeutic value) and PFS (P = 0.005) and between ∆BV and PFS (P = 0.044); a positive correlation existed between ∆aCEC and ∆BV. Therefore, both aCEC and tumor BV can serve as predictors, and detection of both indicators can help evaluate the chemo-antiangiogenic efficacy in NSCLC more accurately.
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Affiliation(s)
- Jing Wang
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
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