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Guleria K, Kaur S, Mahajan D, Sambyal V, Sudan M, Uppal MS. Impact of VEGFA promoter polymorphisms on esophageal cancer risk in North-West Indians: a case-control study. Genes Genomics 2022; 44:923-936. [PMID: 35767183 DOI: 10.1007/s13258-022-01269-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/05/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Angiogenesis play a critical role in the development and progression of tumors in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most important endothelial cell mitogen which plays a critical role in normal physiological and tumor angiogenesis. OBJECTIVES The objective of this case-control study was to investigate the association of VEGF-2578C/A, -2549 I/D, and -460T/C promoter polymorphisms with esophageal cancer risk in North-West Indians. METHODS In this study, 200 sporadic esophageal cancer patients and 200 healthy, unrelated, age and gender matched controls were analyzed. The genomic DNA was extracted from blood samples using phenol chloroform method. Genotyping of VEGF- 2549I/D polymorphism was carried out by direct polymerase chain reaction (PCR) whereas VEGF -2578C/A and VEGF-460T/C) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS AA genotype (p = 0.005) and A allele (p = 0.005) VEGF -2578 C/A, II genotype (p = 0.011) and I allele (p = 0.012) of VEGF - 2549 I/D and CC genotype (p = 0.013) and C allele of VEGF-460T/C polymorphisms were significantly associated with increased risk of esophageal cancer. Stratification of data on the basis of gender showed that VEGF -2578 AA genotype (p = 0.001) and A allele (p = 0.001); VEGF -2549 II genotype (p = 0.002) and I allele (p = 0.002) and VEGF- 460CC genotype (p = 0.001) and C allele (p = 0.002) was significantly associated with increased risk of esophageal cancer in female group. Haplotype analysis revealed that A-2578 I- 2549 C- 460 haplotype was significantly associated with increased risk for esophageal cancer in total samples (p = 0.008) as well as in female group (p = 0.001). CONCLUSIONS The results of present study indicate that VEGF -2578C/A, - 2549I/D and -460T/C polymorphisms were significantly associated with increased risk of esophageal cancer in North-West Indians.
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Affiliation(s)
- Kamlesh Guleria
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
| | - Simranjot Kaur
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Deepanshi Mahajan
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Vasudha Sambyal
- Human Cytogenetics Laboratory, Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Meena Sudan
- Department of Radiotherapy, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
| | - Manjit Singh Uppal
- Department of Surgery, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India
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Risk of Posterior Capsular Rupture during Phacoemulsification in Patients with the History of Anti-VEGF Intravitreal Injections: Results from the Pan-American Collaborative Retina Study (PACORES) Group. J Ophthalmol 2021; 2021:5591865. [PMID: 34671489 PMCID: PMC8523249 DOI: 10.1155/2021/5591865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 11/17/2022] Open
Abstract
Purpose To assess the risk for capsular rupture during routine phacoemulsification in patients with a history of anti-VEGF injections and other possible risk modifiers such as treatment patterns, type of anti-VEGF agent, and experience of the surgeon, among others. Methods This study reviewed the medical records of 11,129 patients from 7 different hospitals in 5 countries. The study included 939 patients that underwent routine phacoemulsification and had a history of anti-VEGF therapy. We excluded patients with known risk factors for capsular rupture, as well as patients with a history of other retinal procedures. The study extracted data regarding general demographics, the number of previous injections, type of anti-VEGF agent, details of cataract surgery, and anti-VEGF treatment patterns. Results Overall prevalence of posterior capsular rupture: 7.45% (95% CI: 5.9–9.32%). The mean number of injections per patient was 3.37 ± 2.8. More than 50% of the patients received their last anti-VEGF injection within three months before cataract surgery. The complication rate during intravitreal injections was 1.07%. In the univariate analysis, the experience of the cataract surgeon (inexperience surgeons; OR: 2.93) and the history of prior anti-VEGF therapy (OR: 1.77) were significant risk indicators for PCR (p < 0.05). However, after controlling for age in the multivariate analysis, the trend did not reach a statistical significance. Conclusion The risk for capsular rupture is higher in patients with a history of intravitreal anti-VEGF injections.
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Liu Y, Li CL, Xu QQ, Cheng D, Liu KD, Sun ZQ. Quercetin inhibits invasion and angiogenesis of esophageal cancer cells. Pathol Res Pract 2021; 222:153455. [PMID: 33962176 DOI: 10.1016/j.prp.2021.153455] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Esophageal carcinoma has poor prognosis and novel therapies for esophageal carcinoma are urgently needed. Quercetin is a natural flavonoid compound that can be found in many foods. In this study, we investigated the effects of quercetin on invasion and angiogenesis of esophageal cancer cells. METHODS Human esophageal cancer cell line Eca109 was treated with 5 μg/mL or 10 μg/mL of quercetin. Colony formation assay was performed. Cell migration and invasion were evaluated by wound healing and transwell assays, respectively. Human umbilical vein/vascular endothelium cells (CLR-1730) were treated with Eca109 conditioned medium, and the effects of quercetin on CLR-1730 were evaluated by wound healing and tube formation assays. Protein levels of VEGF-A, MMP9, and MMP2 were determined by Western blotting. RESULTS The ability of colony forming in Eca109 was reduced with the administration of 10 μg/mL quercetin, but there was no difference between the 5 μg/mL quercetin group and control. The migration distance and the number of invasive cells were significantly reduced in the 10 μg/mL quercetin group. At the lower level of quercetin at 5 μg/mL, only the invasion of cells was significantly inhibited. In endothelial cells treated with Eca109 conditioned medium, cell migration and tube forming ability were suppressed. The decreased protein levels of VEGF-A, MMP9, and MMP2 were observed at the 10 μg/mL quercetin group. CONCLUSION Quercetin suppressed the invasion and angiogenesis of esophageal cancer cells, and the effects were associated with the decreased expression of VEGF-A, MMP2, and MMP9.
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Affiliation(s)
- Yue Liu
- Department of Neurosurgery, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| | - Cai-Li Li
- Department of Neurosurgery, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China.
| | - Qian-Qian Xu
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Dan Cheng
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Ke-Di Liu
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Ze-Qun Sun
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
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Agut R, Falomir E, Murga J, Martín-Beltrán C, Gil-Edo R, Pla A, Carda M, Marco JA. Synthesis of Combretastatin A-4 and 3'-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of Their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression. Molecules 2020; 25:molecules25030660. [PMID: 32033084 PMCID: PMC7037732 DOI: 10.3390/molecules25030660] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/29/2020] [Accepted: 02/01/2020] [Indexed: 01/24/2023] Open
Abstract
Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549 cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the parent compound.
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Affiliation(s)
- Raül Agut
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
| | - Eva Falomir
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
- Correspondence: (E.F.); (M.C.); Tel.: +34-964-728-240 (E.F.); +34-964-728-242 (M.C.)
| | - Juan Murga
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
| | - Celia Martín-Beltrán
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
| | - Raquel Gil-Edo
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
| | - Alberto Pla
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
| | - Miguel Carda
- Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, E-12071 Castellón, Spain; (R.A.); (J.M.); (C.M.-B.); (R.G.-E.); (A.P.)
- Correspondence: (E.F.); (M.C.); Tel.: +34-964-728-240 (E.F.); +34-964-728-242 (M.C.)
| | - J. Alberto Marco
- Departamento de Química Orgánica, Universidad de Valencia, E-46100 Valencia, Spain;
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[ 99mTc]3PRGD 2 for integrin receptor imaging of esophageal cancer: a comparative study with [ 18F]FDG PET/CT. Ann Nucl Med 2018; 33:135-143. [PMID: 30392070 DOI: 10.1007/s12149-018-1315-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 10/29/2018] [Indexed: 10/27/2022]
Abstract
OBJECTIVES This study was designed to investigate the efficacy of 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid ([99mTc]3PRGD2) in the evaluation of patients with esophageal cancer. METHODS Twenty-nine patients with a suspected esophageal lesion and for whom definite pathological diagnosis was finally obtained were recruited. Whole-body planar scanning and chest single-photon-emission computed tomography/computed tomography (SPECT/CT) were performed at 30 and 40 min, respectively, after intravenous injection of 11.1 MBq/kg of [99mTc]3PRGD2. 2-Deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) positron-emission tomography/computed tomography (PET/CT) was performed in 1 week. The tumor-to-background ratio (T/B) and the maximum standard uptake value (SUVmax) were calculated for semi-quantitative and quantitative analyses. Integrin αvβ3 was analyzed through immunohistochemistry. RESULTS The T/B, SUVmax and expression of integrin αvβ3 in malignant lesions were higher than those in benign lesions (t = 3.691, P = 0.001; t = 8.271, P = 0.000; t = 3.632, P = 0.001, respectively). There was a significant correlation between T/B and SUVmax in esophageal lesions (r = 0.660, P = 0.000). The expression of integrin αvβ3 was correlated with [99mTc]3PRGD2 uptake (r = 0.782, P = 0.000). In visual analysis, the sensitivity and accuracy of the whole-body planar RGD scan were lower than those of the chest SPECT/CT RGD scan and the [18F]FDG PET/CT scan (x2 = 6.769, P = 0.022). The sensitivity, specificity and accuracy of the chest SPECT/CT RGD scan were similar to those of the [18F] FDG PET/CT scan. In semi-quantitative analysis, the sensitivity, specificity and accuracy of chest SPECT/CT RGD from the receiver operating characteristic (ROC) analysis were 87%, 100% and 94%, respectively [cutoff = 3.1 of T/B, area under the curve (AUC) = 0.957]. Thirteen patients (30 lymph nodes) and 16 patients (105 lymph nodes) were suspected to have lymph node metastases based on the RGD and FDG scans, respectively. CONCLUSION This prospective study demonstrated that [99mTc]3PRGD2 imaging is valuable for the diagnosis and staging of esophageal cancer. It may be less sensitive than [18F]FDG imaging for detecting metastatic lesions in small lymph nodes. The T/B value was correlated with the expression of integrin αvβ3. NIH CLINICALTRIALS.GOV: NCT 02744729.
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Blasco V, Cuñat AC, Sanz-Cervera JF, Marco JA, Falomir E, Murga J, Carda M. Arylureas derived from colchicine: Enhancement of colchicine oncogene downregulation activity. Eur J Med Chem 2018; 150:817-828. [DOI: 10.1016/j.ejmech.2018.03.039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/01/2018] [Accepted: 03/13/2018] [Indexed: 02/07/2023]
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Kim HJ, Oh SC. Novel Systemic Therapies for Advanced Gastric Cancer. J Gastric Cancer 2018; 18:1-19. [PMID: 29629216 PMCID: PMC5881006 DOI: 10.5230/jgc.2018.18.e3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/14/2018] [Accepted: 02/26/2018] [Indexed: 12/27/2022] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein-Barr virus pattern, microsatellite instability status, and programmed death-ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC.
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Affiliation(s)
- Hong Jun Kim
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sang Cheul Oh
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
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Zhu T, Hu X, Wei P, Shan G. Molecular background of the regional lymph node metastasis of gastric cancer. Oncol Lett 2018; 15:3409-3414. [PMID: 29556271 DOI: 10.3892/ol.2018.7813] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 12/04/2017] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the deadliest types of cancer in the world. Lymph node (LN) metastasis is a complex and malignant behavior of GC, involving a sequence of biological processes, including decreased adherence to adjacent cells, extracellular matrix (ECM) degradation and lymphatic channel permeation. LN metastasis is directly associated with the treatment response, local recurrence and long-term survival of patients with GC. Therefore, the molecular mechanisms of LN metastasis in GC development require further investigation. Recently, a large number of clinical studies have focused on the molecular mechanisms and biological markers of tumor invasion and metastasis. However, few articles have broadly summarized LN metastasis in GC, and the molecular mechanisms of LN metastasis are not yet fully understood. In the present review, the molecular mechanisms of LN metastasis in GC will be discussed, including the following aspects: Cell adhesion and movement, ECM degradation, new vessel formation, and molecular pattern differences between metastatic LNs and the primary tumor. This review may lead to a better understanding of LN metastasis in GC, and the identification of new diagnostic markers.
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Affiliation(s)
- Tong Zhu
- Department of Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Xueqian Hu
- Department of Oncology, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang 315000, P.R. China
| | - Pinkang Wei
- Department of Traditional Chinese Medicine, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Guangzhi Shan
- Department of Oncology, Ningbo Municipal Hospital of Traditional Chinese Medicine, Ningbo, Zhejiang 315000, P.R. China
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Olivera-Severo D, Uberti AF, Marques MS, Pinto MT, Gomez-Lazaro M, Figueiredo C, Leite M, Carlini CR. A New Role for Helicobacter pylori Urease: Contributions to Angiogenesis. Front Microbiol 2017; 8:1883. [PMID: 29021786 PMCID: PMC5623709 DOI: 10.3389/fmicb.2017.01883] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/14/2017] [Indexed: 12/29/2022] Open
Abstract
Helicobacter pylori is a pathogen involved in gastric diseases such as ulcers and carcinomas. H. pylori's urease is an important virulence factor produced in large amounts by this bacterium. In previous studies, we have shown that this protein is able to activate several cell types like neutrophils, monocytes, platelets, endothelial cells, and gastric epithelial cells. Angiogenesis is a physiological process implicated in growth, invasion and metastization of tumors. Here, we have analyzed the angiogenic potential of H. pylori urease (HPU) in gastric epithelial cells. No cytotoxicity was observed in AGS, Kato-III, and MKN28 gastric cell lines treated with 300 nM HPU, as evaluated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. As we previously reported in neutrophils, treatment with 300 nM HPU also had an anti-apoptotic effect in gastric epithelial cells leading to a 2.2-fold increase in the levels of Bcl-XL after 6 h, and a decrease of 80% in the content of BAD, after 48 h, two mitochondrial proteins involved in regulation of apoptosis. Within 10 min of exposure, HPU is rapidly internalized by gastric epithelial cells. Treatment of the gastric cells with methyl-β-cyclodextrin abolished HPU internalization suggesting a cholesterol-dependent process. HPU induces the expression of pro-angiogenic factors and the decrease of expression of anti-angiogenic factors by AGS cells. The angiogenic activity of HPU was analyzed using in vitro and in vivo models. HPU induced formation of tube-like structures by human umbilical vascular endothelial cells in a 9 h experiment. In the chicken embryo chorioallantoic membrane model, HPU induced intense neo-vascularization after 3 days. In conclusion, our results indicate that besides allowing bacterial colonization of the gastric mucosa, H. pylori's urease triggers processes that initiate pro-angiogenic responses in different cellular models. Thus, this bacterial urease, a major virulence factor, may also play a role in gastric carcinoma development.
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Affiliation(s)
- Deiber Olivera-Severo
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil.,Biology Department, Universidade Regional Integrada do Alto Uruguai e das Missões, São Luiz Gonzaga, Brazil
| | - Augusto F Uberti
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil.,Institute of Biology, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Miguel S Marques
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Marta T Pinto
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Maria Gomez-Lazaro
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,INEB - Instituto Nacional de Engenharia Biomédica, University of Porto, Porto, Portugal
| | - Céu Figueiredo
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Marina Leite
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Célia R Carlini
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil.,Brain Institute (BRAINS-InsCer), Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil
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Pinto MP, Owen GI, Retamal I, Garrido M. Angiogenesis inhibitors in early development for gastric cancer. Expert Opin Investig Drugs 2017; 26:1007-1017. [PMID: 28770623 DOI: 10.1080/13543784.2017.1361926] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Angiogenesis, or the generation of new blood vessels from pre-existent ones is a critical process for tumor growth and progression. Hence, the development of angiogenesis inhibitors with therapeutic potential has been a central focus for researchers. Most angiogenesis inhibitors target the Vascular Endothelial Growth Factor (VEGF) pathway, however a number of tyrosine kinase inhibitors (TKIs), immunomodulatory drugs (IMiDs) and inhibitors of the mammalian Target-Of-Rapamycin (mTOR) pathway also display antiangiogenic activity. Areas covered: Here we review the effectiveness of a variety of compounds with antiangiogenic properties in preclinical and clinical settings in gastric cancer (GC). Expert opinion: In coming years angiogenesis will remain as a therapeutic target in GC. To date, ramucirumab a monoclonal antibody that targets VEGFR2 is the most successful antiangiogenic tested in clinical studies, and it is now well established as a second-line therapy in GC. The arrival of precision medicine and the success of immune checkpoint inhibitors will increase the number of clinical trials using targeted agents like ramucirumab in combination with immune checkpoint inhibitors. A hypothetical working model that combines ramucirumab with immunotherapy is presented. Also, the impact of nanotechnology and a molecular subtype classification of GC are discussed.
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Affiliation(s)
- Mauricio P Pinto
- a School of Biological Sciences, Department of Physiology , Pontificia Universidad Católica de Chile , Santiago , Chile
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- c School of Chemistry and Biology, Laboratory on the Immunology of Reproduction , Universidad de Santiago de Chile, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Gareth I Owen
- a School of Biological Sciences, Department of Physiology , Pontificia Universidad Católica de Chile , Santiago , Chile
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- d School of Medicine, Department of Hematology and Oncology , Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Ignacio Retamal
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- d School of Medicine, Department of Hematology and Oncology , Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Marcelo Garrido
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- d School of Medicine, Department of Hematology and Oncology , Pontificia Universidad Católica de Chile , Santiago , Chile
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Hsu JT, Chen TD, Chuang HC, Huang SC, Le PH, Chen TH, Lin CJ, Yeh TS. Vascular endothelial growth factor expression is an independent poor prognostic factor for human epidermal growth factor receptor 2 positive gastric cancer. J Surg Res 2017; 208:40-50. [PMID: 27993216 DOI: 10.1016/j.jss.2016.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 08/24/2016] [Accepted: 09/01/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND The positive expression of human epidermal growth factor receptor 2 (HER-2) is phenotypically associated with differentiated gastric cancer (GC) and is a prognostic factor for resectable GC. The aim of this study was to explore the clinical significance of vascular endothelial growth factor (VEGF), protein kinase B, and p38 mitogen-activated protein kinase (MAPK) regarding outcome in patients with HER-2 positive GC, and to analyze the relationship between these molecules and clinicopathologic parameters. MATERIALS AND METHODS Between January 2001 and December 2012, radical-intent gastrectomy specimens from GC patients were evaluated for HER-2 expression by immunohistochemistry (IHC); and with HER-2 expression levels of 2+ were further subjected to fluorescence in situ hybridization analysis. HER-2 positivity was defined by a HER-2 3+ score on IHC or a HER-2 2+ score on IHC and HER-2 amplification by fluorescence in situ hybridization. The expression of VEGF, phosphorylated protein kinase B, and phosphorylated p38 MAPK in HER-2 positive specimens was scored using IHC. RESULTS Fifty-four patients with HER-2 positive stage I-III GCs were identified. Univariate analysis of prognostic factors showed that tumor differentiation, the presence of vascular invasion, and overexpression of p-p38 MAPK, and VEGF significantly affected prognosis. Multivariate analysis identified vascular invasion (hazard ratio = 2.704; 95% confidence interval = 1.074-7.088; P < 0.033) and the overexpression of VEGF (hazard ratio = 2.760; 95% confidence interval = 1.083-6.753; P < 0.035) to be independent prognostic predictors of HER-2 positive GC. CONCLUSIONS VEGF overexpression and the presence of vascular invasion were independent poor prognostic factors for HER-2 positive GCs.
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Affiliation(s)
- Jun-Te Hsu
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Tai-Di Chen
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Huei-Chieh Chuang
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Shih-Chiang Huang
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tsung-Hsing Chen
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chun-Jung Lin
- Department of Gastroenterology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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12
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Garrido M. The safety and efficacy of ramucirumab in combination with paclitaxel for the treatment of advanced gastric or gastro-esophageal junction adenocarcinoma. Expert Rev Anticancer Ther 2016; 16:1005-10. [PMID: 27582051 DOI: 10.1080/14737140.2016.1231576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Gastric cancer (GC) is a health problem. Platinum and fluoropyrimidine-based combinations have been established as first-line drugs used worldwide. However, there are no other options for treatment if first-line therapy fails. Therefore, second-line treatment options are needed. Targeted therapies have optimized the results of chemotherapy, specifically trastuzumab as a first-line and ramucirumab in second-line. AREAS COVERED Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) are involved in the pathogenesis of GC. Clinical studies have evaluated VEGFR-2 blocked in second line. Two phase III trials using ramucirumab alone or associated to paclitaxel have demonstrated that second-line therapy could improve the survival of patients with GC. Expert commentary: VEGF-2 receptor blockade is effective at treating GC. The combination of paclitaxel with ramucirumab can be used to establish an angiogenic blockade in second-line therapy. The magnitude of the treatment effect suggests that this combination should be used as the current standard.
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Affiliation(s)
- Marcelo Garrido
- a Department of Hemato-Oncology , Pontifical Catholic University of Chile , Santiago , Chile
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13
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Tomasello G, Ghidini M, Liguigli W, Ratti M, Toppo L, Passalacqua R. Targeted therapies in gastric cancer treatment: where we are and where we are going. Invest New Drugs 2016; 34:378-93. [PMID: 26873643 DOI: 10.1007/s10637-016-0330-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/09/2016] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.
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Affiliation(s)
- Gianluca Tomasello
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy.
| | - Michele Ghidini
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Wanda Liguigli
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Margherita Ratti
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Laura Toppo
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Rodolfo Passalacqua
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
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14
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Lee SY, Oh SC. Changing strategies for target therapy in gastric cancer. World J Gastroenterol 2016; 22:1179-89. [PMID: 26811656 PMCID: PMC4716029 DOI: 10.3748/wjg.v22.i3.1179] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/08/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.
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15
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Gagliano T, Gentilin E, Tagliati F, Benfini K, Di Pasquale C, Feo C, Falletta S, Riva E, degli Uberti E, Zatelli MC. Inhibition of epithelial growth factor receptor can play an important role in reducing cell growth and survival in adrenocortical tumors. Biochem Pharmacol 2015; 98:639-48. [DOI: 10.1016/j.bcp.2015.10.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 10/15/2015] [Indexed: 12/13/2022]
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16
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Martí-Centelles R, Falomir E, Murga J, Carda M, Marco JA. Inhibitory effect of cytotoxic stilbenes related to resveratrol on the expression of the VEGF, hTERT and c-Myc genes. Eur J Med Chem 2015; 103:488-96. [PMID: 26402726 DOI: 10.1016/j.ejmech.2015.09.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 09/08/2015] [Accepted: 09/09/2015] [Indexed: 01/31/2023]
Abstract
A group of thirty-nine stilbene derivatives, prepared by means of Heck coupling reactions, has been investigated for their cytotoxicity, as well as for their ability to inhibit the production of the vascular endothelial growth factor (VEGF) and the activation of telomerase. The ability of these compounds to inhibit proliferation of two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293) was first determined. Subsequently, we determined the capacity of the compounds to inhibit the secretion of VEGF in the aforementioned cell lines and to downregulate the expression of the VEGF, hTERT and c-Myc genes, the two latter involved in the control of the activation of telomerase. One of the synthetic stilbenes, (E)-4-(4-methoxystyryl)aniline, showed strong cytotoxicity and proved able to cause a marked decrease both in the secretion of VEGF and in the expression of the hTERT and c-Myc genes, in all cases at concentrations in the low nanomolar range.
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Affiliation(s)
| | - Eva Falomir
- Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071, Castellón, Spain.
| | - Juan Murga
- Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071, Castellón, Spain
| | - Miguel Carda
- Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, E-12071, Castellón, Spain.
| | - J Alberto Marco
- Depart. de Q. Orgánica, Univ. de Valencia, E-46100, Burjassot, Valencia, Spain
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17
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Shinya T, Yokota T, Nakayama S, Oki S, Mutoh J, Takahashi S, Sato K. Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice. J Pharmacol Exp Ther 2015; 354:269-78. [PMID: 26126534 DOI: 10.1124/jpet.115.224816] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 06/29/2015] [Indexed: 03/08/2025] Open
Abstract
Angiogenesis, the formation of new blood vessels from pre-existing vessels, is essential for the growth and metastasis of tumors. In this study, we found that l-carbocisteine, a widely used expectorant, potently inhibits angiogenesis in vitro and in vivo. An in vivo Matrigel plug assay revealed that l-carbocisteine (2.5 mg/kg i.p. twice daily) significantly inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. l-Carbocisteine also suppressed VEGF-stimulated proliferation, migration, and formation of capillary-like structures of human umbilical vein endothelial cells (HUVECs). We examined the signaling pathways affected in VEGF-stimulated HUVECs, and found that l-carbocisteine significantly inhibited VEGF-induced phosphorylation of phospholipase C (PLC) γ, protein kinase C (PKC) μ, and extracellular signal-related kinases (ERK) 1/2, which have been shown to be essential for angiogenesis. However, these inhibitory effects of l-carbocisteine were not observed in the HeLa human cervical cancer cell line. An in vivo study of Colon-26 tumor-bearing mice found that tumor volumes were significantly smaller in mice treated with l-carbocisteine (150 mg/kg administered orally twice daily) in comparison with vehicle-treated mice. However, l-carbocisteine had no direct effect on Colon-26 cell proliferation or ERK activation. Collectively, our results suggest that l-carbocisteine inhibits tumor angiogenesis by suppressing PLCγ/PKC/ERK signaling.
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Affiliation(s)
- Tomohiro Shinya
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
| | - Tsubasa Yokota
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
| | - Shiori Nakayama
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
| | - Sayuri Oki
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
| | - Junpei Mutoh
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
| | - Satoru Takahashi
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
| | - Keizo Sato
- Department of Clinical Biochemistry (T.S.,T.Y., S.N., S.O., K.S.) and Second Department of Pharmacology (J.M.), School of Pharmaceutical Science, Kyushu University of Health and Welfare, Nobeoka, Miyazaki, Japan; and Department of Immunobiology, School of Pharmacy and Pharmaceutical Science, Mukogawa Women's University, Nishinomiya, Hyogo, Japan (S.T.)
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18
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Aprile G, Ongaro E, Del Re M, Lutrino SE, Bonotto M, Ferrari L, Rihawi K, Cardellino GG, Pella N, Danesi R, Fasola G. Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight. Crit Rev Oncol Hematol 2015; 95:165-78. [PMID: 25800976 DOI: 10.1016/j.critrevonc.2015.02.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 12/28/2014] [Accepted: 02/24/2015] [Indexed: 12/11/2022] Open
Abstract
Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results.
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Affiliation(s)
- Giuseppe Aprile
- Department of Medical Oncology, University and General Hospital, Udine, Italy.
| | - Elena Ongaro
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Marzia Del Re
- Clinical Pharmacology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | | | - Marta Bonotto
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Laura Ferrari
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Karim Rihawi
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | | | - Nicoletta Pella
- Department of Medical Oncology, University and General Hospital, Udine, Italy
| | - Romano Danesi
- Clinical Pharmacology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Gianpiero Fasola
- Department of Medical Oncology, University and General Hospital, Udine, Italy
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19
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Ciliberto D, Staropoli N, Caglioti F, Gualtieri S, Fiorillo L, Chiellino S, De Angelis AM, Mendicino F, Botta C, Caraglia M, Tassone P, Tagliaferri P. A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate? Cancer Biol Ther 2015; 16:1148-59. [PMID: 26061272 PMCID: PMC4623405 DOI: 10.1080/15384047.2015.1056415] [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: 03/16/2015] [Revised: 05/12/2015] [Accepted: 05/24/2015] [Indexed: 12/15/2022] Open
Abstract
It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p = 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; 95%CI 0.722-0.939; p = 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents.
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Key Words
- ADME, absorption, distribution, metabolism, and excretion
- Ab, monoclonal antibody
- BSC, best supportive care
- CHT, chemotherapy
- EGFR, epidermal growth factor receptor
- GC, gastric cancer
- HER2, human epidermal growth factor receptor 2
- HER3, human epidermal growth factor receptor 3
- MET, mesenchymal epithelial transition factor
- NGS, next generation sequencing
- NSCLC, non-small cell lung cancer
- OR, odds-ratio
- OS, overall survival
- PARP, poly ADP ribose polymerase
- PFS, progression free survival
- PI3K, phosphatidylinositide 3-kinases
- PRISMA, preferred reporting items for systematic reviews and meta-analyses
- RAF, rapidly accelerated fibrosarcoma
- RAS, rat sarcoma viral oncogene homolog
- RCTs, randomized clinical trials
- RR, response rate
- TKI, tyrosine kinase inhibitor
- VEGF, vascular endothelial growth factor
- VEGFR: VEGF receptor
- aGC, advanced gastric cancer
- angiogenesis
- gastric cancer
- mTOR, mammalian target of rapamycin
- mTORC, mTOR complex
- meta-analysis
- randomized clinical trials
- systemic chemotherapy
- targeted pathways
- targeted therapy
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Affiliation(s)
- Domenico Ciliberto
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Nicoletta Staropoli
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Francesca Caglioti
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Simona Gualtieri
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Lucia Fiorillo
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Silvia Chiellino
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Antonina Maria De Angelis
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Francesco Mendicino
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Cirino Botta
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
| | - Michele Caraglia
- Department of Biochemistry; Biophysics and General Pathology; Second University of Naples; Naples, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA
| | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA
| | - Pierosandro Tagliaferri
- Department of Experimental and Clinical Medicine; Magna Græcia University; Campus Salvatore Venuta; Catanzaro, Italy
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20
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Eng L, Azad AK, Qiu X, Kong QQ, Cheng D, Ying N, Tse A, Kuang Q, Dodbiba L, Renouf DJ, Marsh S, Savas S, Mackay HJ, Knox JJ, Darling GE, Wong RK, Xu W, Liu G, Faluyi OO. Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome. Carcinogenesis 2015; 36:956-62. [DOI: 10.1093/carcin/bgv073] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 05/20/2015] [Indexed: 01/13/2023] Open
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21
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Gastric cancer: past progress and present challenges. Gastric Cancer 2015; 18:205-9. [PMID: 25344928 DOI: 10.1007/s10120-014-0437-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 10/05/2014] [Indexed: 02/07/2023]
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22
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Dreikhausen L, Blank S, Sisic L, Heger U, Weichert W, Jäger D, Bruckner T, Giese N, Grenacher L, Falk C, Ott K, Schmidt T. Association of angiogenic factors with prognosis in esophageal cancer. BMC Cancer 2015; 15:121. [PMID: 25885021 PMCID: PMC4362831 DOI: 10.1186/s12885-015-1120-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 02/24/2015] [Indexed: 02/07/2023] Open
Abstract
Background Despite multimodal therapy esophageal cancer often presents with poor prognosis. To improve outcome, tumor angiogenesis and anti-angiogenic therapeutic agents have recently gained importance. However, patient subgroups who benefit from anti-angiogenic therapy are not yet defined. In this retrospective exploratory study we investigated 9 angiogenic factors in patients’ serum and tissue samples with regard to their association with clinicopathological parameters, prognosis and response in patients with locally advanced preoperatively treated esophageal cancer. Methods From 2007 to 2012 preoperative serum and corresponding tumor tissue (n = 54), only serum (n = 20) or only tumor tissue (n = 4) were collected from esophageal squamous cell carcinoma (SCC) (n = 34) and adenocarcinoma of the esophagogastric junction (AEG) (n = 44) staged cT3/4NanyM0/x after preoperative chemo(radio)therapy. Angiogenic cytokine levels in both tissue and serum were measured by multiplex immunoassay. Results Median survival in all patients was 28.49 months. No significant difference was found in survival between SCC and AEG (p = 0.90). 26 patients were histopathological responders. Histopathological response was associated with prognosis (p = 0.05). Angiogenic factors were associated with the following clinicopathological factors: tumor tissue expression of Angiopoietin-2 and Follistatin was higher in SCC compared to AEG (p = 0.022 and p = 0.001). High HGF and Follistatin expression in the tumor tissue was associated with poor prognosis in all patients (p = 0.037 and p = 0.036). No association with prognosis was found in the patients’ serum. Neither patients’ serum nor tumor tissue showed an association between angiogenic factors and response to neoadjuvant therapy. Conclusion Two angiogenic factors (HGF and Follistatin) in posttherapeutic tumor tissue are associated with prognosis in esophageal cancer patients. Biological differences of AEG and SCC with respect to angiogenesis were evident by the different expression of 2 angiogenic factors. Results are promising and should be pursued prospectively, optimally sequentially pre- and posttherapeutically. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1120-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lena Dreikhausen
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Susanne Blank
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Leila Sisic
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Ulrike Heger
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Wilko Weichert
- Department of Pathology, University of Heidelberg, 69120, Heidelberg, Germany.
| | - Dirk Jäger
- National Center of Tumor Diseases, University of Heidelberg, 69120, Heidelberg, Germany.
| | - Thomas Bruckner
- Institute of Medical Biometry, University of Heidelberg, Heidelberg, Germany.
| | - Natalia Giese
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Lars Grenacher
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany.
| | - Christine Falk
- Institute for Transplant Immunology, Hannover Medical School, Hannover, Germany.
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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Tullavardhana T, Akranurakkul P, Ungkitphaiboon W, Songtish D. Vascular endothelial growth factor-C expression as a biomarker of poor prognosis in esophageal squamous cell carcinoma: a meta-analysis. Oncol Res Treat 2015; 38:110-4. [PMID: 25792082 DOI: 10.1159/000380776] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 01/09/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND Vascular endothelial growth factor C (VEGF-C) is involved in the development and progression of tumor angio-/lymphangiogenesis. The purpose of this study is to evaluate whether VEGF-C expression is an indicator of aggressiveness and poor prognosis of esophageal squamous cell carcinoma (ESCC). METHOD A meta-analysis was conducted to investigate the association between VEGF-C expression with clinicopathological characteristics and survival of ESCC patients. The dataset was defined by searching PubMed, Embase, Google Scholar, and the Cochrane database for appropriate articles published until April 2014. RESULT The final analysis was made from 9 studies, including 656 ESCC patients. Positive VEGF-C expression was defined by immunohistochemistry (IHC) or mRNA expression analysis. The results demonstrated that VEGF-C expression was significantly associated with advanced-stage disease (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.37-3.84, P = 0.002), deeper tumor invasion, lymph node metastasis, and lymphatic invasion. The 5-year survival of VEGF-C expression-negative patients was found to be better than that of VEGF-C expression-positive patients (OR = 0.35, 95% CI = 0.21-0.58, P < 0.0001). However, there was no significant association between the VEGF-C expression levels and either poorer tumor differentiation or vascular invasion. CONCLUSION The results of the meta-analysis strongly indicate that VEGF-C expression could function as a marker for predicting the aggressiveness and prognosis of ESCC.
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Martí-Centelles R, Murga J, Falomir E, Carda M, Alberto Marco J. Inhibitory effect of cytotoxic nitrogen-containing heterocyclic stilbene analogues on VEGF protein secretion and VEGF, hTERT and c-Myc gene expression. MEDCHEMCOMM 2015. [DOI: 10.1039/c5md00197h] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Twenty-one nitrogen-containing heterocyclic stilbenes were synthesized. Their cytotoxicity and effect on VEGF protein secretion as well asVEGF,hTERTandc-Mycgene expression were evaluated.
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Affiliation(s)
| | - Juan Murga
- Depart. de Química Inorgánica y Orgánica
- Univ. Jaume I
- E-12071 Castellón
- Spain
| | - Eva Falomir
- Depart. de Química Inorgánica y Orgánica
- Univ. Jaume I
- E-12071 Castellón
- Spain
| | - Miguel Carda
- Depart. de Química Inorgánica y Orgánica
- Univ. Jaume I
- E-12071 Castellón
- Spain
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Bahce I, Huisman MC, Verwer EE, Ooijevaar R, Boutkourt F, Vugts DJ, van Dongen GA, Boellaard R, Smit EF. Pilot study of (89)Zr-bevacizumab positron emission tomography in patients with advanced non-small cell lung cancer. EJNMMI Res 2014; 4:35. [PMID: 26055936 PMCID: PMC4884046 DOI: 10.1186/s13550-014-0035-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 06/26/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The aim of this pilot study was to evaluate whether the uptake of (89)Zr-bevacizumab in non-small cell lung cancer (NSCLC) tumors could be visualized and quantified. The correlation between tumor (89)Zr-bevacizumab uptake and tumor response to antitumor therapy with a bevacizumab-based regimen was explored. METHODS Seven NSCLC patients underwent static PET scans at days 4 and 7 after injection of 36.4 ± 0.9 MBq (mean ± SD) (89)Zr-bevacizumab, prior to commencing carboplatin-paclitaxel-bevacizumab chemotherapy (CPB). Overall survival (OS) and progression-free survival (PFS) to CPB followed by bevacizumab maintenance therapy was correlated to tumor tracer uptake, quantified using peak standardized uptake values (SUVpeak). RESULTS Zr-bevacizumab uptake (SUVpeak) was approximately four times higher in tumor tissues (primary tumor and metastases) than in non-tumor tissues (healthy muscle, lung, and fat) on days 4 and 7. A positive trend but no significant correlation could be found between SUVpeak and OS or PFS. CONCLUSIONS This pilot study shows that (89)Zr-bevacizumab PET imaging in NSCLC is feasible. Further investigation to validate this technique as a predictive biomarker for selecting patients for bevacizumab treatment is warranted.
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Affiliation(s)
- Idris Bahce
- Department of Pulmonary Diseases, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081HV, The Netherlands,
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Aprile G, Giampieri R, Bonotto M, Bittoni A, Ongaro E, Cardellino GG, Graziano F, Giuliani F, Fasola G, Cascinu S, Scartozzi M. The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey. Expert Opin Investig Drugs 2014; 23:925-42. [PMID: 24806575 DOI: 10.1517/13543784.2014.912631] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements. AREAS COVERED While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment. EXPERT OPINION Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.
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Affiliation(s)
- Giuseppe Aprile
- University and General Hospital, Department of Medical Oncology , Piazzale S Maria della Misericordia 1, 33100, Udine , Italy +39 432 559308 ; +39 432 559305 ;
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Zhang Q, Yu C, Peng S, Xu H, Wright E, Zhang X, Huo X, Cheng E, Pham TH, Asanuma K, Hatanpaa KJ, Rezai D, Wang DH, Sarode V, Melton S, Genta RM, Spechler SJ, Souza RF. Autocrine VEGF signaling promotes proliferation of neoplastic Barrett's epithelial cells through a PLC-dependent pathway. Gastroenterology 2014; 146:461-72.e6. [PMID: 24120473 PMCID: PMC3899829 DOI: 10.1053/j.gastro.2013.10.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 10/03/2013] [Accepted: 10/03/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Tumor cells express vascular endothelial growth factor (VEGF), which induces angiogenesis. VEGF also activates VEGF receptors (VEGFRs) on or within tumor cells to promote their proliferation in an autocrine fashion. We studied the mechanisms of autocrine VEGF signaling in Barrett's esophagus cells. METHODS Using Barrett's epithelial cell lines, we measured VEGF and VEGFR messenger RNA and protein, and studied the effects of VEGF signaling on cell proliferation and VEGF secretion. We studied the effects of inhibiting factors in this pathway on levels of phosphorylated phospholipase Cγ1 (PLCG1), protein kinase C, and extracellular signal-regulated kinases (ERK)1/2. We performed immunohistochemical analysis of phosphorylated VEGFR2 on esophageal adenocarcinoma tissues. We studied effects of sunitinib, a VEGFR2 inhibitor, on proliferation of neoplastic cells and growth of xenograft tumors in mice. RESULTS Neoplastic and non-neoplastic Barrett's cells expressed VEGF and VEGFR2 messenger RNA and protein, with higher levels in neoplastic cells. Incubation with recombinant human VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the recombinant human VEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells. Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2. Sunitinib inhibited VEGF signaling in neoplastic cells and reduced weight and volume of xenograft tumors in mice. CONCLUSIONS Neoplastic and non-neoplastic Barrett's epithelial cells have autocrine VEGF signaling. In neoplastic Barrett's cells, VEGF activation of VEGFR2 initiates a PLCG1-protein kinase C-ERK pathway that promotes proliferation and is self-sustaining (by causing more VEGF production). Strategies to reduce autocrine VEGF signaling (eg, with sunitinib) might be used to prevent or treat cancer in patients with Barrett's esophagus.
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Affiliation(s)
- Qiuyang Zhang
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Chunhua Yu
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Sui Peng
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Division of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Hao Xu
- Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Ellen Wright
- Department of Research and Development, VA North Texas Heath Care System, Dallas, Texas
| | - Xi Zhang
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Xiaofang Huo
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Edaire Cheng
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Pediatrics, Children's Medical Center, Dallas, Texas
| | - Thai H Pham
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Kiyotaka Asanuma
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Kimmo J Hatanpaa
- Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Davood Rezai
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Research and Development, VA North Texas Heath Care System, Dallas, Texas
| | - David H Wang
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Venetia Sarode
- Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Shelby Melton
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas
| | - Robert M Genta
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Miraca Life Sciences, Inc., Irving, Texas
| | - Stuart J Spechler
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Rhonda F Souza
- Center for Esophageal Diseases, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
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Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383:31-39. [PMID: 24094768 DOI: 10.1016/s0140-6736(13)61719-5] [Citation(s) in RCA: 1564] [Impact Index Per Article: 142.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. METHODS We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. FINDINGS 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. INTERPRETATION Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. FUNDING ImClone Systems.
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Affiliation(s)
- Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Jiri Tomasek
- Department of Complex Oncology Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Cho Jae Yong
- Department of Medical Oncology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Filip Dumitru
- Oncology Department, Emergency County Hospital "Dr Constantin Opris", Baia Mare, Romania
| | | | - Chanchal Goswami
- Department of Medical Oncology, B P Poddar Hospital and Medical Research, Kolkata, West Bengal
| | - Howard Safran
- Department of Medicine, The Brown University Oncology Group, Brown University, Providence, RI, USA
| | - Lucas Vieira Dos Santos
- Medical Oncology Department, Gastrointestinal Oncology Division, Hospital de Câncer de Barretos and Hemomed Instituto de Oncologia e Hematologia, São Paulo, Brazil
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy
| | - David R Ferry
- Department of Medical Oncology, New Cross Hospital, West Midlands, UK
| | - Bohuslav Melichar
- Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, CzechRepublic
| | - Mustapha Tehfe
- Department of Medical Oncology, Hôpital Notre Dame de CHUM, Montreal, Quebec
| | - Eldar Topuzov
- State Budgetary Educational Institution of Higher Professional Education (SBEIHPE), "Northwest State Medical University na II Mechnikov", Ministry of Healthcare of the Russian Federation, Russia
| | - John Raymond Zalcberg
- Division of Cancer Medicine, Peter McCallum Cancer Centre, East Melbourne, VIC, Australia; Departments of Medicine and Oncology, Faculty of Medicine, University of Melbourne, Australia
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital, London and Surrey, England
| | - William Campbell
- Department of Oncology, Hospital Herrera Llerandi-Clinicas Médicas, Guatemala
| | | | | | | | - Yanzhi Hsu
- ImClone Systems LLC, Bridgewater, NJ, USA
| | | | - Ling Gao
- ImClone Systems LLC, Bridgewater, NJ, USA
| | | | - Josep Tabernero
- Medical Oncology Department Vall d'Hebron University Hospital, UniversitatAutònoma de Barcelona, Barcelona, Spain
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Torijano-Gutiérrez S, Díaz-Oltra S, Falomir E, Murga J, Carda M, Marco JA. Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity. Bioorg Med Chem 2013; 21:7267-74. [DOI: 10.1016/j.bmc.2013.09.064] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 09/22/2013] [Accepted: 09/26/2013] [Indexed: 11/26/2022]
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Abstract
PURPOSE OF REVIEW Our current review aims to outline recent progress in the development of modern targeted therapeutic regimens for esophageal cancer. RECENT FINDINGS Esophageal cancers demonstrate marked molecular heterogeneity. Modern technology increasingly allows us to identify subgroups of patients whose tumors fit particular molecular profiles. Tumor-based human epidermal growth factor receptor 2 (HER-2) analysis has become a standard part of the work-up for patients with tumors of the esophagogastric junction. The anti-HER-2 antibody, trastuzumab, when added to a chemotherapeutic regimen combining a fluoropyrimidine and platinum, provides a survival benefit for those patients with HER-2 overexpression and/or amplification. Despite large coordinated efforts to establish the efficacy of additional targeted therapeutics, to this point minimal additional benefit has been realized in affecting prominent molecular targets, such as vascular endothelial growth factor and epidermal growth factor receptor, in esophageal cancer. Multiple targets of interest remain under investigation with some early encouraging data. These targets include mammalian target of rapamycin, c-MET, insulin like growth factor 1 receptor and cytotoxic T-lymphocyte antigen 4. Additional improvements in therapy may stem from improved patient selection for combinations of standard cytotoxic regimens, such as platinum-based regimens. SUMMARY Targeted therapeutics have yielded early benefit, but further progress will require a deeper understanding of this disease, improved identification of subpopulations who may derive greater benefit, and continued multicenter efforts to conduct the necessary clinical investigations.
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Alattar M, Omo A, Elsharawy M, Li J. Neuropilin-1 expression in squamous cell carcinoma of the oesophagus. Eur J Cardiothorac Surg 2013; 45:514-20. [DOI: 10.1093/ejcts/ezt380] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Ma J, Ma J, Meng Q, Zhao ZS, Xu WJ. Prognostic value and clinical pathology of MACC-1 and c-MET expression in gastric carcinoma. Pathol Oncol Res 2013; 19:821-32. [PMID: 23812675 DOI: 10.1007/s12253-013-9650-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 05/02/2013] [Indexed: 01/03/2023]
Abstract
This study was to assess the expression of MACC-1 and c-MET in gastric cancer, and to correlate this expression with clinicohistological parameters and patient prognosis. Total RNA was extracted from cancer tissue and adjacent normal mucosa from frozen biopsy specimens of 30 patients with gastric cancer, and MACC-1 expression was assessed by RT-PCR. MACC-1 and c-MET protein expression were also assessed in paraffin-embedded tissues obtained from 436 tumor mucosa and 92 normal mucosa specimens by immunohistochemistry. The correlation between MACC-1 and c-MET expression and clinicopathological factors (age, sex, histology, tumor depth, lymph node status and vessel invasion) were also evaluated. RT-PCR analysis revealed that MACC-1 expression was significantly higher in cancerous mucosa compared with normal tissue. Immunohistochemical analysis indicated that MACC-1 and c-MET were moderately or strongly expressed in gastric cancer tissue, whereas expression was weak or absent in non-cancer tissue. Expression of MACC-1 or c-MET was significantly associated with larger tumor size, deeper tumor invasion, presence of lymph node metastasis, lymphatic involvement, venous invasion, distant metastasis and advanced clinical stage. However, only MACC-1 exhibited significantly greater expression in carcinomas from the higher age group. The intensity of MACC-1 and c-MET expression was also positively correlated. Survival analysis of the 436 gastric cancer patients revealed that patients in clinical stages I, II and III exhibiting lower MACC-1 and c-MET expression had a higher 5-year survival rate compared with patients expressing high levels of these proteins. Multivariate analysis revealed that MACC-1 and c-MET may be independent prognostic indexes of gastric carcinoma (P < 0.01). Our findings confirm that MACC-1 and c-MET expression is strongly related to gastric cancer stage and degree of malignancy, and is inversely correlated to patient prognosis. Thus, MACC-1 and c-MET may interact to promote tumorigenesis and their expression may be used as independent prognostic markers in gastric cancer.
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Affiliation(s)
- Jie Ma
- Department of Pathology, Zhejiang Provincal People's Hospital, Hangzhou, Zhejiang, People's Republic of China
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Martí-Centelles R, Cejudo-Marín R, Falomir E, Murga J, Carda M, Alberto Marco J. Inhibition of VEGF expression in cancer cells and endothelial cell differentiation by synthetic stilbene derivatives. Bioorg Med Chem 2013; 21:3010-5. [DOI: 10.1016/j.bmc.2013.03.072] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 03/21/2013] [Accepted: 03/22/2013] [Indexed: 01/02/2023]
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Bittoni A, Faloppi L, Giampieri R, Cascinu S. Selecting the best treatment for an individual patient. Recent Results Cancer Res 2013; 196:307-18. [PMID: 23129382 DOI: 10.1007/978-3-642-31629-6_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Several factors concur in determining outcome for locally advanced gastric cancer patients. Shockingly, geographic origin of the patient seems to play a major role. In Eastern countries, the high level of surgery that can be expected grants a high percentage of success in a strategy that employs surgery as immediate treatment followed by adjuvant chemotherapy, mainly based on oral fluoropyrimidines (S-1 or Capecitabine), with satisfactory results. In Western countries, the expertise of the surgeon maintains its role as predictor of high likelihood of cure. Indeed, patients treated with standard D2 lymph node dissection have a significantly better survival than those who do not obtain the same kind of treatment. For patients who underwent a suboptimal resection (less than a D1) the classical indication is for a combined adjuvant chemoradiotherapy. In patients who obtain a good surgical outcome, the benefit of the addition of adjuvant chemotherapy is still debatable: the gain in survival seems to be small (around 8 % at 5 years) and with noticeable toxicities (usually with dismal compliance for patients treated). On this basis, neoadjuvant treatment is a promising option even if there is a general lack of conclusive data regarding which is the best regimen to use. Even with the limitation of a small number of studies (with difficulties in enrollment), neoadjuvant chemotherapy is usually feasible, allows for a greater chance of receiving chemotherapy at all, and opens the possibility of a downstaging and downsizing of the tumor, allowing an easier surgery. Regarding this strategy preliminary results have also been presented about the addition of monoclonal antibodies. For example, in the TOGA trial, a significant benefit in terms of overall survival, response rate, and progression free survival was observed also for patients with locally advanced gastric cancer and not just for the metastatic ones. In the AVAGAST trial also, the addition of Bevacizumab failed to determine a significant improvement in the primary outcome, overall survival, for patients treated with the combination, but in the subgroup analysis, patients with locally advanced gastric cancer had a significantly better overall survival and response rate. This data was the basis for the newest neoadjuvant trial, of Cunningham et al., the MAGIC2 trial, with the peri-operative use of ECX+Bevacizumab. Finally, an increasing interest in the use of hyperthermic intraperitoneal chemotherapy in other types of solid tumors (including those of the gastrointestinal tract such as colon cancer) has led to evaluate this treatment modality in gastric cancer patients with peritoneal involvement. It should be noted that it is still to be considered an experimental approach, even though it would be intriguing to evaluate if a particular subset of patients, those who are more likely to develop peritoneal metastasis, may benefit from this technique in the adjuvant setting. It should be considered that other than histologic subtype (diffuse vs intestinal) there seems to be a series of polymorphisms of genes usually involved in cell interaction and migration that can explain a different metastatic pattern in resected patients. Further research on these determinants of metastatic spread could be used to select those patients who may benefit from HIPEC and those who may benefit from standard adjuvant or that gain no benefit at all.
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Halmos B, Jia Y, Bokar JA, Fu P, Adelstein DJ, Juergens R, Rodal MB, Dowlati A. A Phase I study of the combination of oxaliplatin/docetaxel and vandetanib for the treatment of advanced gastroesophageal cancer. Invest New Drugs 2013; 31:1244-50. [PMID: 23553066 DOI: 10.1007/s10637-013-9945-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 02/25/2013] [Indexed: 01/25/2023]
Abstract
INTRODUCTION This study aimed to assess the safety and tolerability of the multitargeted tyrosine kinase inhibitor, vandetanib (V), in combination with two chemotherapeutic agents, oxaliplatin (O) and docetaxel (D) in advanced gastroesophageal (GE) cancer. METHODS This was a Phase I study (NCT00732745) with a standard 3+3 dose escalation design. The primary aim was to determine the optimal dose of the combination of vandetanib and OD chemotherapy. RESULTS Initial treatment for the first cohort consisted of oxaliplatin at 100 mg/m2 on day 1, docetaxel at 35 mg/m2 on days 1 and 8 and vandetanib 100 mg PO daily of 21-day treatment cycles. As dose limiting toxicity (DLT) was reached in 2 out of 3 patients in cohort 1 (one grade 3 and one grade 4 diarrhea with dehydration), 6 patients were treated then at dose level -1 (O 80 mg/m2 on day 1, D 30 mg/m2 on days 1 and 8, V 100 mg PO daily days 1-21) in which no further DLTs were observed. This dose was established as maximum tolerated dose and is the recommended phase 2 dose. 8 out of 9 enrolled patients had adenocarcinoma. At dose level 1, 1 of the 3 patients had a documented partial response and 2 patients had stable disease. At dose level -1, 1 of 6 patients achieved a complete response, 2 of 6 patients had stable disease, and 3 of 6 patients had progressive disease. CONCLUSIONS Vandetanib added to oxaliplatin and docetaxel showed manageable toxicity and limited activity in advanced GE cancer.
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Affiliation(s)
- Balazs Halmos
- University Hospitals, Seidman Cancer Center, Case Western Reserve University, Case Comprehensive Cancer Center, Cleveland, OH, USA,
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Anti-vascular endothelial growth factor therapy in the era of personalized medicine. Cancer Chemother Pharmacol 2013; 72:1-12. [PMID: 23463481 DOI: 10.1007/s00280-013-2124-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 02/11/2013] [Indexed: 12/27/2022]
Abstract
PURPOSE To review the role of anti-vascular endothelial growth factor (anti-VEGF) therapies in the personalized medicine era. METHODS We searched PubMed for prospective clinical trials published through October 2012 of anti-VEGF agents approved by the U.S. Food and Drug Administration or the European Medicines Agency. RESULTS The use of anti-VEGF drugs as single agents or in combination with other targeted or cytotoxic agents was associated with improved response rates and progression-free survival. Anti-VEGF therapy exerts its action by blocking tumor vessel formation and, thus, proliferation. Some investigators demonstrated modest to no improvement in overall survival, although the maintenance of anti-VEGF therapy beyond progression was shown to result in longer overall survival. The use of anti-VEGF therapy was associated with adverse events (i.e., thromboembolism, hemorrhage, myocardial infarction, and hypertension) and transformation to a more invasive phenotype. CONCLUSIONS The development of multikinase targeting agents that include anti-VEGF properties warrants further investigation. The role of anti-VEGF therapy is evolving in the era of personalized medicine, and its use needs to be reassessed in tumor types with effective FDA-approved targeted agents, especially in light of its relatively high cost.
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Scl gene construction, expression and effect on hemangioma. Mol Biol Rep 2012; 40:3381-8. [PMID: 23271126 DOI: 10.1007/s11033-012-2415-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Accepted: 12/18/2012] [Indexed: 10/27/2022]
Abstract
Hemangioma is a tumor that causes vascular endothelial cell hyperplasia, which commonly occur in newborns. Angiogenesis inhibitor targets the processes of angiogenesis, including the proliferation of vascular endothelial cells. A DNA sequence named Scl was designed, recombined into Pichia Pastoris, expressed by fermenting the engineered strain in a bioreactor, and purified the recombinant Scl by SP-sepharose fast flow. Scl can inhibit CAM angiogenesis. Only 1 μg of Scl significantly suppressed the growth of CAM blood vessel, similar to that of 25 μg of angiostatin. Scl showed a strong cytotoxicity on hemangioma cell (ATCC CRL No. 2587). After the drug acted for 24 h, the OD 570 measured value of the PBS control group averaged 1.873, whereas that of the Sc1 drug group was 0.692 (P < 0.01). Using the DeadEndTM Fluorometric TUNEL System, the detection results showed that 92 % of hemangioma cell apoptosis was observed in the Scl protein group, but only 1.3 % in the PBS control group (P < 0.01). After 2 weeks of treatment with the hemangioma model (cock's wattle) of the PBS group, 151 blood vessels with 100 views (40×) were obtained, whereas 250 in the PBS group (P < 0.01). During the two-week medication, the hemangioma model of the PBS group increased by 1.18 cm, whereas only 0.58 cm in the Scl drug group (P < 0.01).
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Yin YM, Zhou Y, Shao YF. Targeted therapies for esophageal cancer. Shijie Huaren Xiaohua Zazhi 2012; 20:3499-3504. [DOI: 10.11569/wcjd.v20.i35.3499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer is a highly frequent malignancy, being the fourth leading cause of cancer-related deaths in China. Most patients are initially diagnosed with advanced disease. Despite recent advances in surgical techniques and adjuvant/neoadjuvant radiotherapy and chemotherapy, the prognosis of esophageal cancer is still poor. An emerging understanding of molecular pathways that characterizes cell growth, cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets for cancer therapy. This review focuses on novel targeted treatments for esophageal cancer.
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Zhang C, Gao GR, Lv CG, Zhang BL, Zhang ZL, Zhang XF. Protease-activated receptor-2 induces expression of vascular endothelial growth factor and cyclooxygenase-2 via the mitogen-activated protein kinase pathway in gastric cancer cells. Oncol Rep 2012; 28:1917-23. [PMID: 22941376 DOI: 10.3892/or.2012.1998] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 07/27/2012] [Indexed: 12/29/2022] Open
Abstract
Protease-activated receptor-2 (PAR-2) has shown strong pro-angiogenesis activity physiologically and pathologically. This study aimed to explore PAR-2 regulation of pro-angiogenesis gene expression and the underlying molecular pathways in gastric cancer cells. MKN28 human gastric cancer cells were treated with trypsin, a PAR-2 activator, and subjected to real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting and ELISA for gene expression analyses. ERK1/2 phosphorylation and p38 MAP kinase inhibitors (PD98059 and SB203580, respectively) were used to block their gene activities. PAR-2 mRNA and protein were expressed in MKN-28 cells and activated by trypsin treatment. Trypsin-activated PAR-2 protein significantly enhanced expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) mRNA and protein in gastric cancer cells in a dose- and time-dependent manner. PAR-2 activation also induced the phosphorylation of ERK1/2 and p38 MAP kinase, but the ERK1/2 and p38 inhibitors blocked the activated PAR-2-induced VEGF and COX-2 expression in gastric cancer cells. PAR-2-induced expression of VEGF and COX-2 mRNA and protein in gastric cancer MKN28 cells was mediated by activation of an ERK1/2- and p38 MAP kinase-dependent pathway. Thus, PAR-2 may serve as a promising target for anti-angiogenesis therapy to treat gastric cancer.
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Affiliation(s)
- Cheng Zhang
- Department of General Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110840, PR China
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Abstract
Gastric cancer (GC) is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.
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Affiliation(s)
- Judith Meza-Junco
- Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
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Wong H, Yau T. Targeted therapy in the management of advanced gastric cancer: are we making progress in the era of personalized medicine? Oncologist 2012; 17:346-58. [PMID: 22334453 PMCID: PMC3316920 DOI: 10.1634/theoncologist.2011-0311] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Accepted: 12/19/2011] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients. METHODS AND RESULTS We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2+ AGC. On the other hand, the Avastin® in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration despite a significantly higher response rate and longer progression-free survival time in patients in the bevacizumab arm. Phase III data are awaited for other targeted agents, including cetuximab, panitumumab, lapatinib, and everolimus. CONCLUSION Recent progress in targeted therapy development for AGC has been modest. Further improvement in the outcome of AGC patients will depend on the identification of biomarkers in different patient populations to facilitate the understanding of gastric carcinogenesis, combining different targeted agents with chemotherapy, and unraveling new molecular targets for therapeutic intervention.
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Affiliation(s)
- Hilda Wong
- Division of Hematology and Medical Oncology, Department of Medicine, and
| | - Thomas Yau
- Division of Hematology and Medical Oncology, Department of Medicine, and
- Department of Surgery, Queen Mary Hospital, Hong Kong
- Centre for Cancer Research, The University of Hong Kong, Hong Kong
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Liu HX, Wang ZH. Advances in research of antiangiogenic drugs for gastric cancer. Shijie Huaren Xiaohua Zazhi 2011; 19:3342-3346. [DOI: 10.11569/wcjd.v19.i32.3342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the most common cancer of the digestive system and the first leading cause of cancer deaths in China. Conventional surgery and chemotherapeutic regimens can not significantly improve the poor prognosis of gastric cancer. In recent years, molecular targeted therapy has become a hot topic in the treatment of cancers, and many antiangiogenic drugs for treatment of gastric cancer have been developed, including monoclonal antibodies or soluble receptors that bind and neutralize vascular endothelial growth factor (VEGF), tyrosine kinase receptor inhibitors, and antibodies against VEGF receptors (VEGFRs).
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Targeting angiogenesis in gastroesophageal cancer: industry-sponsored trials are not the answer. World J Surg 2011; 36:118-9. [PMID: 22037693 DOI: 10.1007/s00268-011-1324-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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