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Chan SHY, Khatib Y, Webley S, Layton D, Salek S. Identification of cardiotoxicity related to non-small cell lung cancer (NSCLC) treatments: A systematic review. Front Pharmacol 2023; 14:1137983. [PMID: 37383708 PMCID: PMC10294714 DOI: 10.3389/fphar.2023.1137983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/27/2023] [Indexed: 06/30/2023] Open
Abstract
Introduction: In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart's function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease. Objectives: To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity. Methods: This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients' treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO. Results: A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. Conclusion: The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760.
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Affiliation(s)
- Stefanie Ho Yi Chan
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Yasmin Khatib
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Sherael Webley
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Deborah Layton
- IQVIA UK, London, United Kingdom
- PEPI Consultancy Limited, Southampton, United Kingdom
- University of Keele, Keele, United Kingdom
| | - Sam Salek
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
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2
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Cholesterol-lowering drug pitavastatin targets lung cancer and angiogenesis via suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling. Anticancer Drugs 2021; 31:377-384. [PMID: 32011362 DOI: 10.1097/cad.0000000000000885] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Therapeutic agents that target both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy, particularly in lung cancer due to the critical roles of angiogenesis during lung cancer progression and metastasis. In this work, we showed that pitavastatin, a novel cholesterol-lowering drug, potently inhibited lung cancer cells and angiogenesis. This was achieved by the induction of apoptosis and inhibition of proliferation of lung cancer cells and human lung tumor-associated endothelial cell. Pitavastatin was not only effective to chemo-sensitive but also chemo-resistant lung cancer cells. This was also consistent with the finding that pitavastatin significantly enhanced cisplatin's efficacy in lung cancer xenograft model without causing toxicity in mice. We further showed that pitavastatin inhibited lung tumor angiogenesis in vitro and in vivo through suppressing human lung tumor-associated endothelial cell migration and morphogenesis without affecting adhesion. Mechanistically, we showed that pitavastatin acted on lung cancer cells and human lung tumor-associated endothelial cell through suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling. Our work is the first to demonstrate the inhibitory effects of pitavastatin on Ras-mediated signaling. Our findings provide pre-clinical evidence to repurpose pitavastatin for the treatment of lung cancer.
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Panahi Y, Mohammadzadeh AH, Behnam B, Orafai HM, Jamialahmadi T, Sahebkar A. A Review of Monoclonal Antibody-Based Treatments in Non-small Cell Lung Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:49-64. [PMID: 33725344 DOI: 10.1007/978-3-030-55035-6_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer worldwide. It metastasizes rapidly and has a poor prognosis. The first-line treatment for most patients is a combination of chemotherapy and radiation. In many subjects, using targeted treatments alongside chemoradiation has shown a better outcome in terms of progression and quality of life for patients. These targeted treatments include small biological inhibiting molecules and monoclonal antibodies. In this review, we have assessed studies focused upon the treatment of non-small cell lung cancer. Some therapies are approved, such as bevacizumab and atezolizumab, while some are still in clinical trials, such as ficlatuzumab and ipilimumab, and others have been rejected due to inadequate disease control, such as figitumumab.
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Affiliation(s)
- Yunes Panahi
- Pharmacotherapy Department, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Mohammadzadeh
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Behzad Behnam
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Kerman University of Medical Sciences, Kerman, Iran
| | - Hossein M Orafai
- Faculty of Pharmacy, Department of Pharmaceutics, University of Ahl Al Bayt, Karbala, Iraq
- Faculty of Pharmacy, Department of Pharmaceutics, Al-Zahraa University, Karbala, Iraq
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Faculty of Medicine, Department of Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
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Inhibition of eIF4E signaling by ribavirin selectively targets lung cancer and angiogenesis. Biochem Biophys Res Commun 2020; 529:519-525. [PMID: 32736668 DOI: 10.1016/j.bbrc.2020.05.127] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 05/19/2020] [Indexed: 12/22/2022]
Abstract
Although the introduction of immune- and targeted-therapy has improved the clinical response and outcomes, lung cancer remains a therapeutic challenge. Developing new therapeutics is necessary to improve the treatment of lung cancer. Here, we show that ribavirin, a clinically available anti-viral drug, is an attractive candidate for lung cancer treatment. We show that ribavirin is active against a panel of lung cancer cell lines regardless of molecular and cellular heterogeneity. Notably, the effective concentrations of ribavirin are clinically achievable, display minimal toxicity to normal cells and synergistic effect with paclitaxel. Its potent efficacy and synergism with chemotherapy on cancer cell, and minimal toxicity on normal cells are observed in lung xenograft mouse model. Ribavirin is also an angiogenesis inhibitor as it inhibits capillary network formation, growth and survival of human lung tumor-associated endothelial cell (HLT-EC). The mechanism studies demonstrate that ribavirin acts on lung cancer cells via suppressing eIF4E and mTOR signaling, leading to the subsequent inhibition of eIF4E-mediated protein translation. Our work suggests that ribavirin has advantage than many anti-cancer agents by targeting both tumor cells and angiogenesis. Our work also highlights the therapeutic potential of ribavirin for the treatment of lung cancer.
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5
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London M, Gallo E. Epidermal growth factor receptor (EGFR) involvement in epithelial-derived cancers and its current antibody-based immunotherapies. Cell Biol Int 2020; 44:1267-1282. [PMID: 32162758 DOI: 10.1002/cbin.11340] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/08/2020] [Indexed: 12/17/2022]
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is part of the family of tyrosine kinase receptors. The binding of EGFR to its cognate ligands leads to its autophosphorylation and subsequent activation of the signal transduction pathways involved in regulating cellular proliferation, differentiation, and survival. Accordingly, this receptor carries out both redundant and restricted functions in the germline development of mammals and in the maintenance of various adult tissues. Correspondingly, the loss of EGFR regulation results in many human diseases, with the most notable cancer. This receptor is overexpressed and/or mutated in multiple epithelial-derived tumors, and associated with poor prognosis and survival in cancer patients. Here, we discuss in detail the role of EGFR in specific epithelial-derived cancer pathologies; these include lung cancer, colorectal cancer, and squamous cell carcinomas. The development of multiple anticancer agents against EGFR diminished the progression and metastasis of tumors. Some of the most versatile therapeutic anti-EGFR agents include the monoclonal antibodies (mAbs), demonstrating success in clinical settings when used in combination with cytotoxic treatments, such as chemotherapy and/or radiation. We thus discuss the development and application of two of the most notable therapeutic mAbs, cetuximab, and panitumumab, currently utilized in various EGFR-related epithelial cancers.
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Affiliation(s)
- Max London
- Department of Molecular Genetics, Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
| | - Eugenio Gallo
- Department of Molecular Genetics, Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada
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Ezzeldin E, Iqbal M, Al-Salahi R, El-Nahhas T. Development and validation of a UPLC-MS/MS method for determination of motesanib in plasma: Application to metabolic stability and pharmacokinetic studies in rats. J Pharm Biomed Anal 2019; 166:244-251. [DOI: 10.1016/j.jpba.2019.01.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/13/2018] [Accepted: 01/12/2019] [Indexed: 01/05/2023]
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7
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AbdElhameid MK, Labib MB, Negmeldin AT, Al-Shorbagy M, Mohammed MR. Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors. J Enzyme Inhib Med Chem 2018; 33:1472-1493. [PMID: 30191744 PMCID: PMC6136361 DOI: 10.1080/14756366.2018.1503654] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/21/2018] [Accepted: 07/16/2018] [Indexed: 12/26/2022] Open
Abstract
In this work, design, synthesis, and screening of thiophene carboxamides 4-13 and 16-23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.
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Affiliation(s)
- Mohammed K. AbdElhameid
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Madlen B. Labib
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed T. Negmeldin
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Department of Pharmaceutical Sciences College of Pharmacy, Gulf Medical University, Gulf Medical University, Ajman, UAE
| | - Muhammad Al-Shorbagy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Pharmacology and Toxicology Department, School of Pharmacy, NewGiza University, Egypt
| | - Manal R. Mohammed
- Department of Radiation Biology, National Center for Radiation Research and Technology, Cairo, Egypt
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Agustoni F, Suda K, Yu H, Ren S, Rivard CJ, Ellison K, Caldwell C, Rozeboom L, Brovsky K, Hirsch FR. EGFR-directed monoclonal antibodies in combination with chemotherapy for treatment of non-small-cell lung cancer: an updated review of clinical trials and new perspectives in biomarkers analysis. Cancer Treat Rev 2018; 72:15-27. [PMID: 30445271 DOI: 10.1016/j.ctrv.2018.08.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 07/30/2018] [Accepted: 08/03/2018] [Indexed: 02/08/2023]
Abstract
Lung cancer still represents one of the most common and fatal neoplasm, accounting for nearly 30% of all cancer-related deaths. Targeted therapies based on molecular tumor features and programmed death-1 (PD-1)/programmed death ligand-1 (PDL-1) blockade immunotherapy have offered new therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC). Activation of the epidermal growth factor receptor (EGFR)-pathway promotes tumor growth and progression, including angiogenesis, invasion, metastasis and inhibition of apoptosis, providing a strong rationale for targeting this pathway. EGFR expression is detected in up to 85% of NSCLC and has been demonstrated to be associated with poor prognosis. Two approaches for blocking EGFR signaling are available: prevention of ligand binding to the extracellular domain with monoclonal antibodies (mAbs) and inhibition of the intracellular tyrosine kinase activity with small molecules. There is a strong rationale to consider the tumor's level of EGFR expression as one of the most significant predictive biomarkers in this setting. In this paper we provide an update focusing on the current status of EGFR-directed mAbs use for the treatment of patients with advanced NSCLC, through a review of all clinical trials involving anti-EGFR mAbs in combination with chemotherapy (CT) for advanced disease and with chemo-radiotherapy for stage III disease. Here we also discuss the current status of predictive biomarkers for anti-EGFR mAbs when added to first-line CT in patients with advanced NSCLC. Finally, we focused on the relevance of EGFR fluorescence in situ hybridization (FISH)+ and immunohistochemistry (IHC)-Score ≥ 200 as predictive biomarkers for the selection of patients who would be most likely to derive a clinical benefit from treatment with CT in combination with anti-EGFR mAbs, with particular reference also to histology.
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Affiliation(s)
- Francesco Agustoni
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kenichi Suda
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Division of Thoracic Surgery, Department of Surgery, Kindai University, Faculty of Medicine, Osaka-Sayama, Japan
| | - Hui Yu
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Shengxiang Ren
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Christopher J Rivard
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kim Ellison
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Charles Caldwell
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Leslie Rozeboom
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kristine Brovsky
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Fred R Hirsch
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
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Qu J, Zhang Y, Chen X, Yang H, Zhou C, Yang N. Newly developed anti-angiogenic therapy in non-small cell lung cancer. Oncotarget 2017. [PMID: 29515799 PMCID: PMC5839380 DOI: 10.18632/oncotarget.23755] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Angiogenesis and its role in the growth and development of non-small cell lung cancer (NSCLC) metastases has become an increasing clinical problem. Vascular endothelial growth factor (VEGF) plays a key role in advanced NSCLC. To some extent, anti-angiogenic therapies acquired some efficacy in combination with chemotherapy, target therapy and immunotherapy. However, the reliable clinical benefit obtained with these drugs is still questionable and often quantitatively limited. In this review, the authors highlight the data obtained from first-line, second-line, epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) target therapy and immunotherapy in NSCLC patients who are treated with anti-angiogenic molecules in advanced NSCLC. The purpose of this study is to help us truly understand how to best use angiogenesis therapy in advanced NSCLC.
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Affiliation(s)
- Jingjing Qu
- Department of Lung Cancer and Gastrointestinal Oncology Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Yongchang Zhang
- Department of Lung Cancer and Gastrointestinal Oncology Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Xue Chen
- Department of Lung Cancer and Gastrointestinal Oncology Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Haiyan Yang
- Department of Lung Cancer and Gastrointestinal Oncology Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Chunhua Zhou
- Department of Lung Cancer and Gastrointestinal Oncology Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Nong Yang
- Department of Lung Cancer and Gastrointestinal Oncology Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
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Wu X, Li F, Wang X, Li C, Meng Q, Wang C, Huang J, Chen S, Zhu Z. Antibiotic bedaquiline effectively targets growth, survival and tumor angiogenesis of lung cancer through suppressing energy metabolism. Biochem Biophys Res Commun 2017; 495:267-272. [PMID: 29107691 DOI: 10.1016/j.bbrc.2017.10.136] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 10/25/2017] [Indexed: 12/26/2022]
Abstract
Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF). We further demonstrate that bedaquiline acts on lung cancer cells and HLT-EC via inhibiting mitochondrial respiration and glycolysis, leading to ATP reduction and oxidative stress. Consistently, oxidative damage on DNA, protein and lipid were detected in cells exposed to bedaquiline. Importantly, the results obtained in in vitro cell culture are reproducible in in vivo xenograft lung cancer mouse model, confirming that bedaquiline suppresses lug tumor growth and angiogenesis, and increases oxidative stress. Our findings demonstrating that energy depletion is effectively against lung tumor cells and angiogenesis. Our work also provide pre-clinical evidence to repurpose antibiotic bedaquiline for lung cancer treatment.
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Affiliation(s)
- Xiaomu Wu
- Department of Neurology, The Central Hospital of Wuhan, Wuhan, People's Republic of China
| | - Fajiu Li
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Xiaojiang Wang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Chenghong Li
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Qinghua Meng
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Chuanhai Wang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Jie Huang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Shi Chen
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China
| | - Ziyang Zhu
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, People's Republic of China.
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Zhong L, Yang J, Cao Z, Chen X, Hu Y, Li L, Yang S. Preclinical pharmacodynamic evaluation of drug candidate SKLB-178 in the treatment of non-small cell lung cancer. Oncotarget 2017; 8:12843-12854. [PMID: 28086226 PMCID: PMC5355060 DOI: 10.18632/oncotarget.14597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 11/23/2016] [Indexed: 02/05/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is a serious life-threatening malignancy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as Gefitinib and Erlotinib, are effective clinical medicines for advanced NSCLC patients harboring EGFR-activating mutations. However, this therapy just benefits a small percentage of sufferers. Worse still, all patients treated with drugs ultimately develop resistance. Hence, there is still an unmet medical need among patients with NSCLC. In this account, we report a novel multikinase inhibitor SKLB-178, which potently inhibits both EGFR-activating and resistant mutations, as well as the activities of Src and VEGFR2 kinases. SKLB-178 potently inhibited cancer cell growth in both Gefitinib-sensitive and resistant NSCLC cells. Meanwhile, SKLB-178 significantly suppressed the migration, invasion and tube formation of endothelial cells, and the growth of intersegmental vessel in zebrafish. The in vivo pharmacodynamic studies further demonstrated that SKLB-178 had wider potency than Gefitinib, and could significantly prolong survival of animals in A549 experimental metastasis model. These advantages together with the low toxicity of SKLB-178 indicate that SKLB-178 deserves to be further developed as a potential drug candidate for NSCLC therapy.
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Affiliation(s)
- Lei Zhong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University/Collaborative Innovation Center of Biotherapy, Sichuan 610041, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Sichuan 610072, China
| | - Jiao Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University/Collaborative Innovation Center of Biotherapy, Sichuan 610041, China
| | - Zhixing Cao
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Sichuan 611137, China
| | - Xin Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University/Collaborative Innovation Center of Biotherapy, Sichuan 610041, China
| | - Yiguo Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University/Collaborative Innovation Center of Biotherapy, Sichuan 610041, China
| | - Linli Li
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of pharmacy, Sichuan University, Sichuan 610041, China
| | - Shengyong Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University/Collaborative Innovation Center of Biotherapy, Sichuan 610041, China
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Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JCH, Hara K, Asato T, Nakagawa K. Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2017; 35:3662-3670. [PMID: 28902534 DOI: 10.1200/jco.2017.72.7297] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m2 IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months ( P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% ( P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer.
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Affiliation(s)
- Kaoru Kubota
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Hiroshige Yoshioka
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Fumihiro Oshita
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Toyoaki Hida
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Kiyotaka Yoh
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Hidetoshi Hayashi
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Terufumi Kato
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Hiroyasu Kaneda
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Kazuhiko Yamada
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Hiroshi Tanaka
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Yukito Ichinose
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Keunchil Park
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Eun Kyung Cho
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Kyung-Hee Lee
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Chih-Bin Lin
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - James Chih-Hsin Yang
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Kaori Hara
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Takayuki Asato
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
| | - Kazuhiko Nakagawa
- Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China
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Li F, Huang J, Ji D, Meng Q, Wang C, Chen S, Wang X, Zhu Z, Jiang C, Shi Y, Liu S, Li C. Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer. Oncol Lett 2017; 14:89-96. [PMID: 28693139 PMCID: PMC5494938 DOI: 10.3892/ol.2017.6103] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 03/03/2017] [Indexed: 02/02/2023] Open
Abstract
Tumor angiogenesis is essential during lung cancer development and targeting angiogenesis may possess a potential therapeutic value. The present study demonstrates that azithromycin, a Food and Drug Administration-approved antibiotic drug, is a novel tumor angiogenesis inhibitor. Azithromycin inhibits capillary network formation of human lung tumor associated-endothelial cells (HLT-ECs) in vitro and in vivo. It significantly inhibits HLT-EC adhesion and vascular endothelial growth factor (VEGF)-induced proliferation of HLT-ECs in a dose-dependent manner without affecting migration. In addition, azithromycin induces apoptosis of HLT-ECs even in the presence of VEGF. Notably, azithromycin inhibits proliferation and induces apoptosis in multiple lung cancer cell lines to a significantly reduced extent compared with in HLT-ECs, suggesting that HLT-ECs are more susceptible to azithromycin treatment. In a lung tumor xenograft model, azithromycin significantly inhibits tumor growth and its anti-tumor activities are achieved by suppressing angiogenesis. Notably, the inhibitory effects of azithromycin on angiogenesis are associated with its ability to suppress VEGF-induced activation of VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), focal adhesion kinase, and disruption of focal adhesion assembly and actin stress fiber formation in HLT-ECs. The present study identifies that azithromycin targets VEGFR2-mediated focal adhesion and PI3K/Akt signaling pathways in HLT-ECs, leading to the suppression of angiogenesis and lung tumor growth.
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Affiliation(s)
- Fajiu Li
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Jie Huang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Dongyuan Ji
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Qinghua Meng
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Chuanhai Wang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Shi Chen
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Xiaojiang Wang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Zhiyang Zhu
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Cheng Jiang
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Yi Shi
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Shuang Liu
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
| | - Chenghong Li
- Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
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Motesanib plus carboplatin/paclitaxel in patients with advanced squamous non-small-cell lung cancer: results from the randomized controlled MONET1 study. J Thorac Oncol 2015; 9:1154-61. [PMID: 25157768 DOI: 10.1097/jto.0000000000000227] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol. 2012;30:2829-2836). Herein, we report data from the squamous cohort. METHODS Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/mL•min/paclitaxel, 200 mg/m) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival. RESULTS Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months). CONCLUSIONS Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC.
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Tebbutt N, Kotasek D, Burris HA, Schwartzberg LS, Hurwitz H, Stephenson J, Warner DJ, Chen L, Hsu CP, Goldstein D. Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer. Cancer Chemother Pharmacol 2015; 75:993-1004. [PMID: 25772756 DOI: 10.1007/s00280-015-2694-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 01/26/2015] [Indexed: 12/31/2022]
Abstract
PURPOSE This study assessed the safety, efficacy, and pharmacokinetics of motesanib, a multitargeted small molecule angiogenesis inhibitor, with and without panitumumab, in combination with FOLFIRI or FOLFOX in patients with metastatic colorectal cancer (mCRC). METHODS This open-label, phase 1b, two-part, multicenter study in patients with mCRC and ≤1 prior treatment evaluated escalating doses (50, 75, 100, or 125 mg QD, 75 mg BID) of motesanib with panitumumab and chemotherapy (Part 1) and the target dose of motesanib with chemotherapy (Part 2). RESULTS At 17 sites in the USA and Australia, 119 patients were enrolled between December 2004 and February 2010. In Part 1 [motesanib plus panitumumab/FOLFIRI (n = 36) or plus panitumumab/FOLFOX (n = 17)], all motesanib doses tested were tolerated and 125 mg QD was deemed the target dose. Following toxicity results for combination therapy in other trials, panitumumab was withdrawn from the study. Part 2 evaluated motesanib 125 mg with chemotherapy [FOLFIRI (n = 37); FOLFOX (n = 29)]. The primary endpoint, objective response rate in patients with measurable disease by RECIST, was 20 % overall and was higher among patients receiving first-line (27 % overall; FOLFOX, 24 %; FOLFIRI, 27 %) compared with second-line therapy (14 % overall; FOLFOX, 0 %; FOLFIRI, 20 %). The most common adverse events were diarrhea, nausea, fatigue, and hypertension. We observed a low rate of cholecystitis [3 of 119 (2.5 %)], a known adverse event of motesanib and other small molecule VEGF inhibitors. CONCLUSIONS Motesanib 125 mg QD in combination with FOLFIRI or FOLFOX chemotherapy was tolerated and demonstrated modest efficacy in first-/second-line mCRC.
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Affiliation(s)
- Niall Tebbutt
- Department of Medical Oncology, Austin Health, Heidelberg, VIC, 3084, Australia,
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Gaumann AKA, Kiefer F, Alfer J, Lang SA, Geissler EK, Breier G. Receptor tyrosine kinase inhibitors: Are they real tumor killers? Int J Cancer 2015; 138:540-54. [PMID: 25716346 DOI: 10.1002/ijc.29499] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 02/13/2015] [Indexed: 12/11/2022]
Abstract
Inhibiting tumor growth by targeting the tumor vasculature was first proposed by Judah Folkman almost 40 years ago. Since then, different approaches and numerous drugs and agents have been developed to achieve this goal, either with the aim of inhibiting tumor neoangiogenesis or normalizing the tumor vasculature. Among the most promising therapeutic targets are receptor tyrosine kinases (RTKs), some of which are predominantly expressed on tumor endothelial cells, although they are sometimes also present on tumor cells. The majority of RTK inhibitors investigated over the past two decades competes with ATP at the active site of the kinase and therefore block the phosphorylation of intracellular targets. Some of these drugs have been approved for therapy, whereas others are still in clinical trials. Here, we discuss the scientific basis, current status, problems and future prospects of RTK inhibition in anti-tumor therapy.
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Affiliation(s)
- Andreas K A Gaumann
- Institute of Pathology Kaufbeuren-Ravensburg, Kaufbeuren, Germany
- Institute of Pathology, University of Regensburg, Medical Center, Regensburg, Germany
| | - Friedemann Kiefer
- Mammalian Cell Signaling Laboratory, Max Planck Institute for Molecular Biomedicine, Münster, North Rhine-Westphalia, Germany
| | - Joachim Alfer
- Institute of Pathology Kaufbeuren-Ravensburg, Kaufbeuren, Germany
| | - Sven A Lang
- Department of Surgery, University of Regensburg, Medical Center, Regensburg, Germany
| | - Edward K Geissler
- Department of Surgery, University of Regensburg, Medical Center, Regensburg, Germany
| | - Georg Breier
- Institute of Pathology, Technical University Dresden, Dresden, Germany
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Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JEA, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol 2015; 16:328-37. [PMID: 25701171 DOI: 10.1016/s1470-2045(15)70046-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). METHODS We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Luis Paz-Ares
- Instituto de Biomedicina de Sevilla-IBIS (Hospital Virgen del Rocío/Universidad de Sevilla/CSIC), Sevilla, Spain; Hospital Universitario Doce de Octubre and CNIO Lung Cancer Unit, Madrid, Spain.
| | | | - Tudor E Ciuleanu
- Institute of Oncology and University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | | | | | - Andrzej Kazarnowicz
- Samodzielny Publiczny Zespól Gruźlicy i Chorób Pluc w Olsztynie, Olsztyn, Poland
| | | | | | | | - Lucio Crino
- Ospedale Santa Maria della Misericordia, Perugia, Italy
| | - Martin Reck
- LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Rodryg Ramlau
- Poznan University of Medical Sciences, Wielkopolskie Centrum Pulmonologii i Torakochirurgii, Poznan, Poland
| | | | - Christian Schumann
- Department of Internal Medicine II, University Clinic Ulm, Ulm, Germany; Klinik für Pneumologie, Thoraxonkologie, Schlaf-und Beatmungsmedizin, Kempten-Oberallgäu, Germany
| | | | - Álvaro E Lessa
- Hospital Santa Izabel-Santa Casa de Misericordia da Bahia, Nazare, Nazare, Brazil
| | - Mircea Dediu
- Institute of Oncology Bucharest, Bucharest, Romania
| | - Beatrix Bálint
- Csongrád Megye Mellkasi Betegségek Szakkórháza, Deszk, Hungary
| | | | | | | | - Fred R Hirsch
- University of Colorado, Division of Medical Oncology, Aurora, CO, USA
| | - Nick Thatcher
- The Christie Hospital, National Health Services Trust, Manchester, UK
| | - Mark A Socinski
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA
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Rijavec E, Genova C, Barletta G, Biello F, Dal Bello MG, Coco S, Truini A, Vanni I, Alama A, Boccardo F, Grossi F. Efficacy of motesanib diphosphate in non-small-cell lung cancer. Expert Opin Pharmacother 2014; 15:1771-80. [PMID: 25032887 DOI: 10.1517/14656566.2014.938639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Angiogenesis plays a crucial role in the proliferation and in the metastatic spread of tumour cells. Several agents with anti-angiogenic activity have been tested in advanced non-small-cell lung cancer (NSCLC) patients. Motesanib (AMG 706) is a promising anti-angiogenic multi-targeted tyrosine kinase inhibitor (TKI), which has been investigated as a monotherapy or in combination with chemotherapy, in several types of cancer. AREAS COVERED We have reviewed the literature, and we have presented the results of clinical trials that have investigated the administration of motesanib in advanced NSCLC patients. EXPERT OPINION Encouraging results have been described with the administration of motesanib as first-line treatment in combination with carboplatin and paclitaxel in Asian patients with non-squamous advanced NSCLC. Further studies are needed in order to identify the predictive biomarkers of response and to select patients who may benefit from this anti-angiogenic treatment.
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Affiliation(s)
- Erika Rijavec
- IRCCS AOU San Martino IST - Istituto Nazionale per la Ricerca sul Cancro, UOS Tumori Polmonari , Largo Rosanna Benzi No 10, 16132 Genova , Italy +39 0105600665 ; +39 0105600795 ;
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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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Kubota K, Ichinose Y, Scagliotti G, Spigel D, Kim JH, Shinkai T, Takeda K, Kim SW, Hsia TC, Li RK, Tiangco BJ, Yau S, Lim WT, Yao B, Hei YJ, Park K. Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis. Ann Oncol 2014; 25:529-36. [PMID: 24419239 DOI: 10.1093/annonc/mdt552] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%). CONCLUSION In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P. CLINICAL TRIAL NUMBER NCT00460317.
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Affiliation(s)
- K Kubota
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo
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LC-ESI-MS/MS determination of simotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor: application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 947-948:168-72. [PMID: 24440798 DOI: 10.1016/j.jchromb.2013.12.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 12/09/2013] [Accepted: 12/19/2013] [Indexed: 11/23/2022]
Abstract
Simotinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor. This study presented a sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry method using erlotinib as internal standard for the determination of simotinib in human plasma. The method involved a simple liquid-liquid extraction using diethyl ether. The analytes were separated with isocratic gradient elution on an Agilent TC-C18 column (4.6 × 150 mm, 5 μm). Mass spectrometric detector equipped with electrospray ionization source was carried out in the mode of multiple reaction monitoring (MRM). The monitored transitions were m/z 501.2→182.1 for simotinib and m/z 394.4→278.1 for erlotinib. The calibration curve of simotinib was established over the range of 2.058-3000 μg L(-1) (r(2)=0.9924). The intra- and inter-day precisions were all less than 10%, and all the biases were not more than 7%. This validated method was then successfully applied to a pharmacokinetic study involving twelve healthy Chinese volunteers. The mean Cmax and Tmax for simotinib were 254.79±98.30 μg L(-1) and 1.71±0.48 h, respectively. Plasma concentrations declined with a t1/2 of 5.37±2.32 h. AUC0-t and AUC0→∞ values obtained were 1262.59±501.41 μg L(-1) h and 1329.95±517.42 μg L(-1) h, respectively.
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Rosen LS, Lipton L, Price TJ, Belman ND, Boccia RV, Hurwitz HI, Stephenson JJ, Wirth LJ, McCoy S, Hei YJ, Hsu CP, Tebbutt NC. The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors. BMC Cancer 2013; 13:242. [PMID: 23679351 PMCID: PMC3688238 DOI: 10.1186/1471-2407-13-242] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 04/26/2013] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary "sludge" in Arms A/B/C was 39%/36%/27%. CONCLUSIONS Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. TRIAL REGISTRATION ClinicalTrials.gov NCT00448786.
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Affiliation(s)
- Lee S Rosen
- Department of Medicine, University of California Los Angeles, Santa Monica, CA, USA.
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Schilder RJ, Sill MW, Lankes HA, Gold MA, Mannel RS, Modesitt SC, Hanjani P, Bonebrake AJ, Sood AK, Godwin AK, Hu W, Alpaugh RK. A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: a Gynecologic Oncology Group study. Gynecol Oncol 2013; 129:86-91. [PMID: 23321064 PMCID: PMC3712785 DOI: 10.1016/j.ygyno.2013.01.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 01/02/2013] [Accepted: 01/08/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1-3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. PATIENTS AND METHODS Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125 mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). RESULTS The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. CONCLUSIONS The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.
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Affiliation(s)
- R J Schilder
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
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Mendivil AN, Rodriguez PM, Felip E. Angiogenesis, multitarget kinase inhibitors and non-small cell lung cancer: a lesson from MONET1 trial. Transl Lung Cancer Res 2013; 2:E13-6. [PMID: 25806210 DOI: 10.3978/j.issn.2218-6751.2012.09.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 09/26/2012] [Indexed: 11/14/2022]
Affiliation(s)
- Alejandro Navarro Mendivil
- Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Pablo Martinez Rodriguez
- Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Enriqueta Felip
- Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain
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Majem M, Pallarès C. An update on molecularly targeted therapies in second- and third-line treatment in non-small cell lung cancer: focus on EGFR inhibitors and anti-angiogenic agents. Clin Transl Oncol 2013; 15:343-57. [DOI: 10.1007/s12094-012-0964-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Accepted: 10/19/2012] [Indexed: 12/22/2022]
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Coxon A, Ziegler B, Kaufman S, Xu M, Wang H, Weishuhn D, Schmidt J, Sweet H, Starnes C, Saffran D, Polverino A. Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non-small-cell lung cancer xenograft models. Mol Cancer 2012; 11:70. [PMID: 22992329 PMCID: PMC3515409 DOI: 10.1186/1476-4598-11-70] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 09/03/2012] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Non-small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations. RESULTS Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro. CONCLUSIONS These data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.
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Affiliation(s)
- Angela Coxon
- Department of Oncology Research, Amgen Inc, One Amgen Centre Drive, Thousand Oaks, CA 91320, USA.
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De Boer RH, Kotasek D, White S, Koczwara B, Mainwaring P, Chan A, Melara R, Ye Y, Adewoye AH, Sikorski R, Kaufman PA. Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer. Breast Cancer Res Treat 2012; 135:241-52. [PMID: 22872523 PMCID: PMC3413817 DOI: 10.1007/s10549-012-2135-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 06/08/2012] [Indexed: 01/06/2023]
Abstract
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m2 on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m2. Forty-six patients were enrolled and 45 received ≥1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.
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Affiliation(s)
- Richard H De Boer
- Department of Medical Oncology, Royal Melbourne Hospital, Grattan St, 2nd Floor, Parkville, Melbourne, VIC 3050, Australia.
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Kono SA, Heasley LE, Doebele RC, Camidge DR. Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer. Curr Cancer Drug Targets 2012; 12:107-23. [PMID: 22165970 DOI: 10.2174/156800912799095144] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 09/27/2011] [Accepted: 10/11/2011] [Indexed: 01/20/2023]
Abstract
The treatment of advanced non � small cell lung cancer (NSCLC) increasingly involves the use of molecularly targeted therapy with activity against either the tumor directly, or indirectly, through activity against host-derived mechanisms of tumor support such as angiogenesis. The most well studied signaling pathway associated with angiogenesis is the vascular endothelial growth factor (VEGF) pathway, and the only antiangiogenic agent currently approved for the treatment of NSCLC is bevacizumab, an antibody targeted against VEGF. More recently, preclinical data supporting the role of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) signaling in angiogenesis have been reported. The platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways may also stimulate tumor growth directly through activation of downstream mitogenic signaling cascades. In addition, 1 or both of these pathways have been associated with resistance to agents targeting the epidermal growth factor receptor (EGFR) and VEGF. A number of agents that target FGF and/or PDGF signaling are now in development for the treatment of NSCLC. This review will summarize the potential molecular roles of PDGFR and FGFR in tumor growth and angiogenesis, as well as discuss the current clinical status of PDGFR and FGFR inhibitors in clinical development.
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Affiliation(s)
- S A Kono
- Aerodigestive and Thoracic Tumor Program, Winship Cancer Institute, Emory University, Room C3005, 1365 Clifton Road NE, Atlanta, GA 30322, USA.
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Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 2012; 30:2829-36. [PMID: 22753922 DOI: 10.1200/jco.2011.41.4987] [Citation(s) in RCA: 148] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
PURPOSE We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non-small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma. PATIENTS AND METHODS Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m(2)) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS. RESULTS A total of 1,090 patients with nonsquamous NSCLC were randomly assigned (arms A/B, n = 541 of 549); of those, 890 had adenocarcinoma (n = 448 of 442). Median OS in arms A and B was 13.0 and 11.0 months, respectively (hazard ratio [HR], 0.90; 95% CI, 0.78 to 1.04; P = .14); median OS for the adenocarcinoma subset was 13.5 and 11.0 months, respectively (HR, 0.88; 95% CI, 0.75 to 1.03; P = .11). In descriptive analyses (arms A v B), median PFS was 5.6 months versus 5.4 months (P = < .001); ORR was 40% versus 26% (P < .001). There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs (arms A and B, 73% and 59%, respectively) and grade 5 AEs (14% and 9%, respectively) was higher with motesanib treatment. CONCLUSION Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset.
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Gori B, Ricciardi S, Fulvi A, Del Signore E, de Marinis F. New oral multitargeted antiangiogenics in non-small-cell lung cancer treatment. Future Oncol 2012; 8:559-73. [DOI: 10.2217/fon.12.48] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Non-small-cell lung cancer is a particularly aggressive cancer. Combination chemotherapy remains the standard therapy for patients with advanced or metastatic disease. However, despite the available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process controlled by a delicate balance between pro- and antiangiogenic factors and their receptors; tumors induce angiogenesis by disrupting this balance and secreting various growth factors. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes monoclonal antibodies against VEGF and VEGF receptor and small molecule inhibitors of VEGF tyrosine kinase activity (tyrosine kinase inhibitors). Tyrosine kinase inhibitors are orally active, small molecules that represent a new class of drugs with a relatively high safety profile. They are targeted therapies that play their anticancer role interfering with specific cell signaling. This review focuses on such oral antiangiogenic agents that have been approved and are in advanced clinical development for the treatment of patients with advanced non-small-cell lung cancer.
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Affiliation(s)
- Bruno Gori
- Oncological–Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy
| | - Serena Ricciardi
- Oncological–Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy
| | - Alberto Fulvi
- Oncological–Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy
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31
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Zhou C. Multi-targeted tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: an era of individualized therapy. Transl Lung Cancer Res 2012; 1:72-7. [PMID: 25806157 PMCID: PMC4367587 DOI: 10.3978/j.issn.2218-6751.2011.12.04] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 12/19/2011] [Indexed: 01/07/2023]
Abstract
Multi-targeted tyrosine kinase inhibitors (TKIs) have played an increasingly important role in the treatment of non-small cell lung cancer (NSCLC). Many recently published phase III trials have shown bittersweet efficacies of these drugs. How to optimize the efficacies of TKIs has been a hot topic in the era of individualized therapy. In this article, we review the up-to-dated advances in research on the application of TKIs for NSCLC treatment.
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Affiliation(s)
- Caicun Zhou
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
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32
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Development and clinical application of a LC-MS/MS method for simultaneous determination of various tyrosine kinase inhibitors in human plasma. Clin Chim Acta 2012; 413:143-9. [DOI: 10.1016/j.cca.2011.09.012] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 09/08/2011] [Accepted: 09/08/2011] [Indexed: 01/27/2023]
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Gori B, Ricciardi S, Fulvi A, Intagliata S, Signore ED, de Marinis F. New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120) and beyond. Ther Clin Risk Manag 2011; 7:429-40. [PMID: 22241943 PMCID: PMC3253753 DOI: 10.2147/tcrm.s22079] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named "vascular disrupting agents," tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances.
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Affiliation(s)
- Bruno Gori
- Oncological-Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy
| | - Serena Ricciardi
- Oncological-Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy
| | - Alberto Fulvi
- Oncological-Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy
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de Mello RA, Marques DS, Medeiros R, Araújo AM. Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol 2011; 2:367-76. [PMID: 22087435 PMCID: PMC3215775 DOI: 10.5306/wjco.v2.i11.367] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 10/10/2011] [Accepted: 10/17/2011] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is currently the leading cause of cancer death in Western nations. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers, and adenocarcinoma is the predominant histological type. Despite the intensive research carried out on this field and therapeutic advances, the overall prognosis of these patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Nowadays, pharmacogenetics and pharmacogenomics represent the key to successful treatment. Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma: one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor (EGFR). The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR (erlotinib and gefitinib) and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs. This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR, K-Ras and EGFR targeted therapies in NSCLC tumor behavior.
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Affiliation(s)
- Ramon Andrade de Mello
- Ramon Andrade de Mello, Dânia Sofia Marques, Department of Medical Oncology, Portuguese Oncology Institute, Porto 4200-072, Portugal
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Zhou C. [Current status and future direction of multi-targeted drugs in the era of personalized therapy--overview of advances in multi-targeted therapy in non-small cell lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2011; 14:874-9. [PMID: 22104223 PMCID: PMC5999997 DOI: 10.3779/j.issn.1009-3419.2011.11.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Revised: 10/28/2011] [Indexed: 11/30/2022]
Abstract
Multi-targeted tyrosine kinase inhibitors (TKIs) play important roles in the treatment of non-small cell lung cancer (NSCLC). Recently, results of several large phase III studies have been published, showing bittersweet efficacy of multi-targeted TKIs. In the era of personalized therapy, optimal use of multi-targeted TKIs is worthy of further investigation. In this review, we summarized current clinical development and future direction of multi-targeted TKIs in NSCLC.
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Affiliation(s)
- Caicun Zhou
- Department of Oncology, Shanghai Pulmonary Hospital, Affiliated to Tongji University School of Medicine, Shanghai 200433, China.
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Bruce D, Tan PH. Blocking the interaction of vascular endothelial growth factor receptors with their ligands and their effector signaling as a novel therapeutic target for cancer: time for a new look? Expert Opin Investig Drugs 2011; 20:1413-34. [DOI: 10.1517/13543784.2011.611801] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Raghav KPS, Blumenschein GR. Motesanib and advanced NSCLC: experiences and expectations. Expert Opin Investig Drugs 2011; 20:859-69. [PMID: 21534718 DOI: 10.1517/13543784.2011.579103] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Benefits from conventional chemotherapy in NSCLC have plateaued. Accordingly, sizeable efforts have gone into developing novel therapies. Tumor angiogenesis mediated principally by VEGF has emerged as an alluring target because of its vital role in tumor growth, sustenance and metastasis. The Eastern Cooperative Oncology Group (ECOG) trial E4599 showed significant improvement in overall survival with addition of bevacizumab, a VEGF monoclonal antibody, to cytotoxic chemotherapy in metastatic NSCLC. A number of compounds targeting tumor angiogenesis have since gone into preclinical and clinical testing. The multifaceted nature of cancer has led to development of multitarget tyrosine kinase inhibitors (MTKIs) that target several pathways concomitantly. Motesanib, an orally administered potent small molecule, targets VEGFR 1 - 3, PDGFR and KIT. Oral bioavailability and preliminary evidence of activity make this compound an appealing choice for additional investigations. AREAS COVERED This review summarizes the background of angiogenesis and rationale for targeting the VEGF pathway in NSCLC. The authors also review recent clinical trial data evaluating motesanib. EXPERT OPINION VEGF is a validated target in NSCLC. In early trials motesanib has shown promising activity in NSCLC with tolerable toxicity profile. A Phase III trial with motesanib in combination with chemotherapy is ongoing.
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Affiliation(s)
- Kanwal Pratap Singh Raghav
- Hematology and Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Faculty Center (FC11.2049), Unit 0421, Houston, TX 77030, USA
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Burris H, Stephenson J, Otterson GA, Stein M, McGreivy J, Sun YN, Ingram M, Ye Y, Schwartzberg LS. Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-Cisplatin in patients with advanced cancer. JOURNAL OF ONCOLOGY 2011; 2011:853931. [PMID: 21559248 PMCID: PMC3087488 DOI: 10.1155/2011/853931] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 02/12/2011] [Indexed: 02/04/2023]
Abstract
Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m(2)) and cisplatin (75 mg/m(2)) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
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Affiliation(s)
- Howard Burris
- Sarah Cannon Research Institute, Nashville, TN 37203, USA
| | - Joe Stephenson
- Cancer Center of the Carolinas, Greenville, SC 29605, USA
| | | | - Mark Stein
- Robert Wood Johnson University Hospital, UMDNJ, New Brunswick, NJ 08903, USA
| | | | | | | | - Yining Ye
- Amgen Inc., South San Francisco, CA 94080, USA
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Blumenschein GR, Kabbinavar F, Menon H, Mok TSK, Stephenson J, Beck JT, Lakshmaiah K, Reckamp K, Hei YJ, Kracht K, Sun YN, Sikorski R, Schwartzberg L. A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer. Ann Oncol 2011; 22:2057-2067. [PMID: 21321086 DOI: 10.1093/annonc/mdq731] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab. PATIENTS AND METHODS Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). RESULTS ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies. CONCLUSIONS The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.
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Affiliation(s)
- G R Blumenschein
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston.
| | - F Kabbinavar
- Department of Medicine, University of California Los Angeles Medical Center, Los Angeles; Hematology/Oncology, University of California Los Angeles Medical Center, Los Angeles; Translational Oncology Research International, Los Angeles, USA
| | - H Menon
- Department of Medical Oncology, Tata Memorial Center, Mumbai, India
| | - T S K Mok
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | | | - J T Beck
- Highlands Oncology Group, Fayetteville, USA
| | - K Lakshmaiah
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - K Reckamp
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte
| | | | | | - Y-N Sun
- Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks
| | | | - L Schwartzberg
- Department of Hematology and Oncology, The West Clinic, Memphis, USA
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Cai J, Han S, Qing R, Liao D, Law B, Boulton ME. In pursuit of new anti-angiogenic therapies for cancer treatment. FRONT BIOSCI-LANDMRK 2011; 16:803-14. [PMID: 21196204 PMCID: PMC3627482 DOI: 10.2741/3721] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite advances in surgery, radiation therapy, and chemotherapy, patients with cancer have a poor prognosis. Sustained aberrant tumor angiogenesis and metastasis is a major obstacle for effective cancer treatment. Just a few years ago, few would argue that one of the key success stories of the modern cancer medicine were the anti-angiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway approved by FDA. This initial success inspired many researchers to search for new anti-angiogenic targets and drugs with the hope that one day, anti-angiogenic therapy might really become the panacea for cancer patients. Unfortunately, the limited clinical benefits achieved with anti-angiogenic drugs conflicts with the widely accepted notion that angiogenesis is a key event in tumor progression. Emerging data indicate that unique characteristics of the tumor vasculature within the tumor microenvironment may hold the key for success of anti-angiogenic therapy. In particular, the molecular and cellular alterations that sustain aberrant tumor angiogenesis in the face of angiogenic inhibitors represents novel targets for rationally designing and improving current anti-angiogenic strategies.
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Affiliation(s)
- Jun Cai
- Department of Anatomy and Cell Biology University of Florida, Gainesville, FL 32610, USA
| | - Song Han
- Department of Surgery University of Florida, Gainesville, FL 32610, USA
| | - Ruan Qing
- Department of Anatomy and Cell Biology University of Florida, Gainesville, FL 32610, USA
| | - Daiqing Liao
- Department of Anatomy and Cell Biology University of Florida, Gainesville, FL 32610, USA
| | - Brian Law
- Department of Pharmacology and Therapeutics; University of Florida, Gainesville, FL 32610, USA
| | - Michael E. Boulton
- Department of Anatomy and Cell Biology University of Florida, Gainesville, FL 32610, USA
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Nguewa PA, Calvo A, Pullamsetti SS, Banat GA, Grimminger F, Savai R. Tyrosine kinase inhibitors with antiangiogenic properties for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs 2010; 20:61-74. [PMID: 21142806 DOI: 10.1517/13543784.2011.541153] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
IMPORTANCE OF THE FIELD The 5-year survival rate in NSCLC remains < 15% in spite of new chemotherapeutic regimens and targeted therapies. Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties show promise as a new therapeutic approach for NSCLC in recent studies. AREAS COVERED IN THIS REVIEW This article reviews significant preclinical and clinical studies related to TKI therapy. Many drugs that target tyrosine kinases involved in tumor angiogenesis have recently been developed. Results of preclinical experiments and clinical trials for NSCLC are quite promising. However, response rates are low and the duration of therapeutic response is short. Mechanisms of resistance may reduce the efficacy of TKI therapy, and biomarkers of response are needed to select patients who are more likely to benefit from the therapy. Studies in mice have shown that antiangiogenic TKIs may increase metastasis, although no clear clinical evidence supports these results. WHAT THE READER WILL GAIN An understanding of the mechanisms of action, clinical trial results, biomarkers of response, adverse effects and possible mechanisms of resistance associated with novel TKI therapy in NSCLC. TAKE HOME MESSAGE More preclinical and clinical research on the efficacy of TKIs in treating NSCLC is needed, but present results offer great hope for patients.
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Affiliation(s)
- Paul A Nguewa
- Center for Applied Medical Research (CIMA), Division of Oncology, University of Navarra, Pamplona, 31008, Spain
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Abstract
Claiming more than 150,000 lives each year, lung cancer is the deadliest cancer in the USA. First-line treatments in lung cancer include surgical resection and chemotherapy, the latter of which offers only modest survival benefits at the expense of often severe and debilitating side effects. Recent advances in elucidating the molecular biology of lung carcinogenesis have elucidated novel drug targets, and treatments are rapidly evolving into specialized agents that hone in on specific aspects of the disease. Of particular interest is blocking tumor growth by targeting the physiological processes surrounding angiogenesis, pro-tumorigenic growth factor activation, anti-apoptotic cascades and other cancer-promoting signal transduction events. This article looks at several areas of interest to lung cancer therapeutics and considers the current state of affairs surrounding the development of these therapies.
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Affiliation(s)
- M Roshni Ray
- Thoracic Oncology Program, Department of Surgery, University of California, San Francisco, CA 94115, USA
| | - David Jablons
- Thoracic Oncology Program, Department of Surgery, University of California, San Francisco, CA 94115, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
| | - Biao He
- Thoracic Oncology Program, Department of Surgery, University of California, San Francisco, CA 94115, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
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