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1
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Feng H, Zhou K, Yuan Q, Liu Z, Zhang T, Chen H, Xu B, Sun Z, Han Z, Liu H, Yu S, Chen T, Li G, Zhou W, Yu J, Huang W, Jiang Y. Noninvasive Assessment of Vascular Endothelial Growth Factor and Prognosis in Gastric Cancer Through Radiomic Features. Clin Transl Gastroenterol 2025; 16:e00802. [PMID: 39787380 PMCID: PMC11932601 DOI: 10.14309/ctg.0000000000000802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 12/04/2024] [Indexed: 01/12/2025] Open
Abstract
INTRODUCTION Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, with delayed diagnosis often limiting effective treatment options. This study introduces a novel, noninvasive radiomics-based approach using [18F] FDG PET/CT (fluorodeoxyglucose positron emission tomography/computed tomography) to predict vascular endothelial growth factor (VEGF) status and survival in patients with GC. The ability to noninvasively assess these parameters can significantly influence therapeutic decisions and outcomes. METHODS We conducted a retrospective study involving patients diagnosed with GC, stratified into training, validation, and test groups. Each patient underwent a [18F] FDG PET/CT scan, and radiomic features were extracted using dedicated software. A Radiomics Score (RS) was calculated, serving as a predictor for VEGF status. Statistical analyses included logistic regression and Cox proportional hazards models to evaluate the predictive power of RS on survival outcomes. RESULTS The developed radiomics model demonstrated high predictive accuracy, with the RS formula achieving an area under the receiver operating characteristic curve of 0.861 in the training cohort and 0.857 in the validation cohort for predicting VEGF status. The model also identified RS as an independent prognostic factor for survival, where higher RS values correlated with poorer survival rates. DISCUSSION The findings underscore the potential of [18F] FDG PET/CT radiomics in transforming the management of GC by providing a noninvasive means to assess tumor aggressiveness and prognosis through VEGF status. This model could facilitate earlier and more tailored therapeutic interventions, potentially improving survival outcomes in a disease marked by typically late diagnosis and limited treatment success.
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Affiliation(s)
- Hao Feng
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangneng Zhou
- College of Computer Science, Nankai University, Tianjin, China
| | - Qingyu Yuan
- Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiwei Liu
- Department of PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Taojun Zhang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Benjamin Xu
- Lynbrook High School, San Jose, California, USA
| | - Zepang Sun
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhen Han
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Liu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shitong Yu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tao Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guoxin Li
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Wenlan Zhou
- Department of PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weicai Huang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuming Jiang
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
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Kalofonou F, Kalofonou M, Dimitrakopoulos FI, Kalofonos H. Monoclonal Antibodies in Metastatic Gastro-Esophageal Cancers: An Overview of the Latest Therapeutic Advances. Int J Mol Sci 2025; 26:1090. [PMID: 39940858 PMCID: PMC11816984 DOI: 10.3390/ijms26031090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/18/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Monoclonal antibodies (mAbs) have completely changed the face of oncology over the last 50 years, and they have contributed to a major breakthrough in terms of cancer therapy. Esophageal and gastric cancers, the eighth and fifth most commonly diagnosed types of cancer worldwide, respectively, have lately, been managed more effectively, with the introduction of new therapeutic treatment strategies, especially mAbs. Combination treatments and new molecules have changed the face of the disease, while more therapies are getting approved on a daily basis. This review aims to analyse the major up-to-date clinical trials using mAbs and immunotherapy for the treatment of advanced gastro-esophageal cancers.
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Affiliation(s)
- Foteini Kalofonou
- Department of Medical Oncology, The Royal Marsden NHS Trust, London SW3 6JJ, UK
| | - Melpomeni Kalofonou
- Centre of Bio-Inspired Technology, Department of Electrical and Electronic Engineering, Imperial College London, London SW7 2AZ, UK
| | | | - Haralabos Kalofonos
- Division of Oncology, Department of Medicine, Medical School, University of Patras, 26504 Rion, Greece
- Division of Oncology, Olympion General Clinic, 26443 Patras, Greece
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Wu LW, Jang SJ, Shapiro C, Fazlollahi L, Wang TC, Ryeom SW, Moy RH. Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics. Target Oncol 2024; 19:845-865. [PMID: 39271577 PMCID: PMC11557641 DOI: 10.1007/s11523-024-01097-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 09/15/2024]
Abstract
Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.
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Affiliation(s)
- Lawrence W Wu
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, Room 956, New York, NY, 10032, USA
| | - Sung Joo Jang
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Cameron Shapiro
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Sandra W Ryeom
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Ryan H Moy
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, Room 956, New York, NY, 10032, USA.
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Shen G, Jia X, Qi T, Hu Z, Xiao A, Liu Q, He K, Guo W, Zhang D, Li W, Cao G, Li G, Tian J, Huang X, Hu Y. Data-Driven Design of Triple-Targeted Protein Nanoprobes for Multiplexed Imaging of Cancer Lymphatic Metastasis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2405877. [PMID: 38889909 DOI: 10.1002/adma.202405877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/06/2024] [Indexed: 06/20/2024]
Abstract
Targeted imaging of cancer lymphatic metastasis remains challenging due to its highly heterogeneous molecular and phenotypic diversity. Herein, triple-targeted protein nanoprobes capable of specifically binding to three targets for imaging cancer lymphatic metastasis, through a data-driven design approach combined with a synthetic biology-based assembly strategy, are introduced. Specifically, to address the diversity of metastatic lymph nodes (LNs), a combination of three targets, including C-X-C motif chemokine receptor 4 (CXCR4), transferrin receptor protein 1 (TfR1), and vascular endothelial growth factor receptor 3 (VEGFR3) is identified, leveraging machine leaning-based bioinformatics analysis and examination of LN tissues from patients with gastric cancer. Using this identified target combination, ferritin nanocage-based nanoprobes capable of specifically binding to all three targets are designed through the self-assembly of genetically engineered ferritin subunits using a synthetic biology approach. Using these nanoprobes, multiplexed imaging of heterogeneous metastatic LNs is successfully achieved in a polyclonal lymphatic metastasis animal model. In 19 freshly resected human gastric specimens, the signal from the triple-targeted nanoprobes significantly differentiates metastatic LNs from benign LNs. This study not only provides an effective nanoprobe for imaging highly heterogeneous lymphatic metastasis but also proposes a potential strategy for guiding the design of targeted nanomedicines for cancer lymphatic metastasis.
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Affiliation(s)
- Guodong Shen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaohua Jia
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Department of Ultrasound, Shuozhou Grand Hospital of Shanxi Medical University, Shuozhou, 036000, China
| | - Tianyi Qi
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhenhua Hu
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Anqi Xiao
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Qiqi Liu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Keyu He
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Weihong Guo
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Dan Zhang
- Center of Biomedical Analysis, Tsinghua University, Beijing, 100084, China
| | - Wanjun Li
- Department of Pathology, Affiliated 3201 Hospital of Xi'an Jiaotong University, Hanzhong, 723000, China
| | - Genmao Cao
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Guoxin Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jie Tian
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing, 100191, China
| | - Xinglu Huang
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yanfeng Hu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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Chen X, Zhang Z, Wang L, Zhang J, Zhao T, Cai J, Dang Y, Guo R, Liu R, Zhou Y, Wei R, Lou X, Xia F, Ma D, Li F, Dai J, Li F, Xi L. Homodimeric peptide radiotracer [ 68Ga]Ga-NOTA-(TMVP1) 2 for VEGFR-3 imaging of cervical cancer patients. Eur J Nucl Med Mol Imaging 2024; 51:2338-2352. [PMID: 38411667 DOI: 10.1007/s00259-024-06661-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 02/19/2024] [Indexed: 02/28/2024]
Abstract
PURPOSE Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).
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Affiliation(s)
- Xi Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhenzhong Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- Department of Gynecologic Oncology, Henan Provincial Cancer Hospital, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ling Wang
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingjing Zhang
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tianzhi Zhao
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jiong Cai
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yonghong Dang
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruixia Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Rui Liu
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
| | - Rui Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
| | - Xiaoding Lou
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Fan Xia
- State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China
| | - Ding Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China
| | - Fang Li
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
| | - Fei Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
| | - Ling Xi
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
- National Clinical Research Centre for Obstetrics and Gynecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430034, China.
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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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Thakur A, Rana M, Mishra A, Kaur C, Pan CH, Nepali K. Recent advances and future directions on small molecule VEGFR inhibitors in oncological conditions. Eur J Med Chem 2024; 272:116472. [PMID: 38728867 DOI: 10.1016/j.ejmech.2024.116472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/18/2024] [Accepted: 04/30/2024] [Indexed: 05/12/2024]
Abstract
"A journey of mixed emotions" is a quote that best describes the progress chart of vascular endothelial growth factor receptor (VEGFR) inhibitors as cancer therapeutics in the last decade. Exhilarated with the Food and Drug Administration (FDA) approvals of numerous VEGFR inhibitors coupled with the annoyance of encountering the complications associated with their use, drug discovery enthusiasts are on their toes with an unswerving determination to enhance the rate of translation of VEGFR inhibitors from preclinical to clinical stage. The recently crafted armory of VEGFR inhibitors is a testament to their growing dominance over other antiangiogenic therapies for cancer treatment. This review perspicuously underscores the earnest attempts of the researchers to extract the antiproliferative potential of VEGFR inhibitors through the design of mechanistically diverse structural assemblages. Moreover, this review encompasses sections on structural/molecular properties and physiological functions of VEGFR, FDA-approved VEGFR inhibitors, and hurdles restricting the activity range/clinical applicability of VEGFR targeting antitumor agents. In addition, tactics to overcome the limitations of VEGFR inhibitors are discussed. A clear-cut viewpoint transmitted through this compilation can provide practical directions to push the cart of VEGFR inhibitors to advanced-stage clinical investigations in diverse malignancies.
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Affiliation(s)
- Amandeep Thakur
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan
| | - Mandeep Rana
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan
| | - Anshul Mishra
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan
| | - Charanjit Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Chun-Hsu Pan
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
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8
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Chauhan S, Sen S, Irshad K, Kashyap S, Pushker N, Meel R, Sharma MC. Receptor tyrosine kinase gene expression profiling of orbital rhabdomyosarcoma unveils MET as a potential biomarker and therapeutic target. Hum Cell 2024; 37:297-309. [PMID: 37914903 DOI: 10.1007/s13577-023-00993-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 10/06/2023] [Indexed: 11/03/2023]
Abstract
Receptor tyrosine kinases (RTKs) serve as molecular targets for the development of novel personalized therapies in many malignancies. In the present study, expression pattern of receptor tyrosine kinases and its clinical significance in orbital RMS has been explored. Eighteen patients with histopathologically confirmed orbital RMS formed part of this study. Comprehensive q-PCR gene expression profiles of 19 RTKs were generated in the cases and controls. The patients were followed up for 59.53 ± 20.93 years. Clustering and statistical analysis tools were applied to identify the significant combination of RTKs associated with orbital rhabdomyosarcoma patients. mRNA overexpression of RTKs which included MET, AXL, EGFR was seen in 60-80% of cases; EGFR3, IGFR2, FGFR1, RET, PDGFR1, VEGFR2, PDGFR2 in 30-60% of cases; and EGFR4, FGFR3,VEGFR3 and ROS,IGFR1, EGFR1, FGFR2, VEGFR1 in 10-30% of cases. Immunoexpression of MET was seen in 89% of cases. A significant association was seen between MET mRNA and its protein expression. In all the cases MET gene expression was associated with worst overall survival (P = 0.03).There was a significant correlation of MET mRNA expression with RET, ROS, AXL, FGFR1, FGFR3, PDGFR1, IGFR1, VEGFR2, and EGFR3 genes. Association between MET gene and collective expression of RTKs was further evaluated by semi-supervised gene cluster analysis and Principal component analysis, which showed well-separated tumor clusters. MET gene overexpression could be a useful biomarker for identifying high risk orbital rhabdomyosarcoma patients. Well-separated tumor clusters confirmed the association between MET gene and collective expression of RTK genes. Therefore, the therapeutic potential of multi-kinase inhibitors targeting MET and the 9 other significant RTKs needs to be explored.
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Affiliation(s)
- Sheetal Chauhan
- Ocular Pathology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, Room No. 725, New Delhi, 110029, India
| | - Seema Sen
- Ocular Pathology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, Room No. 725, New Delhi, 110029, India.
| | - Khushboo Irshad
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Seema Kashyap
- Ocular Pathology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, Room No. 725, New Delhi, 110029, India
| | - Neelam Pushker
- Ophthalmoplasty Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Rachna Meel
- Ophthalmoplasty Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Mehar Chand Sharma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
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9
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Bae SH, Hwang T, Han MR. Unraveling the hypoxia modulating potential of VEGF family genes in pan-cancer. Genomics Inform 2023; 21:e44. [PMID: 37852616 PMCID: PMC10788353 DOI: 10.5808/gi.23061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 10/20/2023] Open
Abstract
Tumor hypoxia, oxygen deprivation state, occurs in most cancers and promotes angiogenesis, enhancing the potential for metastasis. The vascular endothelial growth factor (VEGF) family genes play crucial roles in tumorigenesis by promoting angiogenesis. To investigate the malignant processes triggered by hypoxia-induced angiogenesis across pan-cancers, we comprehensively analyzed the relationships between the expression of VEGF family genes and hypoxic microenvironment based on integrated bioinformatics methods. Our results suggest that the expression of VEGF family genes differs significantly among various cancers, highlighting their heterogeneity effect on human cancers. Across the 33 cancers, VEGFB and VEGFD showed the highest and lowest expression levels, respectively. The survival analysis showed that VEGFA and placental growth factor (PGF) were correlated with poor prognosis in many cancers, including kidney renal cell and liver hepatocellular carcinoma. VEGFC expression was positively correlated with glioma and stomach cancer. VEGFA and PGF showed distinct positive correlations with hypoxia scores in most cancers, indicating a potential correlation with tumor aggressiveness. The expression of miRNAs targeting VEGF family genes, including hsa-miR-130b-5p and hsa-miR-940, was positively correlated with hypoxia. In immune subtypes analysis, VEGFC was highly expressed in C3 (inflammatory) and C6 (transforming growth factor β dominant) across various cancers, indicating its potential role as a tumor promotor. VEGFC expression exhibited positive correlations with immune infiltration scores, suggesting low tumor purity. High expression of VEGFA and VEGFC showed favorable responses to various drugs, including BLU-667, which abrogates RET signaling, an oncogenic driver in liver and thyroid cancers. Our findings suggest potential roles of VEGF family genes in malignant processes related with hypoxia-induced angiogenesis.
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Affiliation(s)
- So-Hyun Bae
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
| | - Taewon Hwang
- Department of Electrical and Electronic Engineering, Yonsei University, Seoul 03722, Korea
| | - Mi-Ryung Han
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
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10
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Vimalraj S, Hariprabu KNG, Rahaman M, Govindasami P, Perumal K, Sekaran S, Ganapathy D. Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis. 3 Biotech 2023; 13:326. [PMID: 37663750 PMCID: PMC10474002 DOI: 10.1007/s13205-023-03719-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 07/13/2023] [Indexed: 09/05/2023] Open
Abstract
The cancer-promoting ligand vascular endothelial growth factor-C (VEGF-C) activates VEGF receptor-3 (VEGFR-3). The VEGF-C/VEGFR-3 axis is expressed by a range of human tumor cells in addition to lymphatic endothelial cells. Activating the VEGF-C/VEGFR-3 signaling enhances metastasis by promoting lymphangiogenesis and angiogenesis inside and around tumors. Stimulation of VEGF-C/VEGFR-3 signaling promotes tumor metastasis in tumors, such as ovarian, renal, pancreatic, prostate, lung, skin, gastric, colorectal, cervical, leukemia, mesothelioma, Kaposi sarcoma, and endometrial carcinoma. We discuss and update the role of VEGF-C/VEGFR-3 signaling in tumor development and the research is still needed to completely comprehend this multifunctional receptor.
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Affiliation(s)
- Selvaraj Vimalraj
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology, Madras, Chennai, India
| | | | - Mostafizur Rahaman
- Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451 Saudi Arabia
| | - Periyasami Govindasami
- Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451 Saudi Arabia
| | - Karthikeyan Perumal
- Department of Chemistry and Biochemistry, The Ohio State University, 151 W. Woodruff Ave, Columbus, OH 43210 USA
| | - Saravanan Sekaran
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu 600 077 India
| | - Dhanraj Ganapathy
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu 600 077 India
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11
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Wu SM, Jan YJ, Tsai SC, Pan HC, Shen CC, Yang CN, Lee SH, Liu SH, Shen LW, Chiu CS, Arbiser JL, Meng M, Sheu ML. Targeting histone deacetylase-3 blocked epithelial-mesenchymal plasticity and metastatic dissemination in gastric cancer. Cell Biol Toxicol 2023; 39:1873-1896. [PMID: 34973135 PMCID: PMC10547655 DOI: 10.1007/s10565-021-09673-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 10/13/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND PURPOSE Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. EXPERIMENTAL APPROACH Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. KEY RESULTS HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. CONCLUSIONS AND IMPLICATIONS Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress-activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.
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Affiliation(s)
- Sheng-Mao Wu
- Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Road, 250, Taichung, Taiwan
| | - Yee-Jee Jan
- Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shih-Chuan Tsai
- Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hung-Chuan Pan
- Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chin-Chang Shen
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Cheng-Ning Yang
- Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shu-Hua Lee
- Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Road, 250, Taichung, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Li-Wei Shen
- Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Road, 250, Taichung, Taiwan
| | - Chien-Shan Chiu
- Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jack L Arbiser
- Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta Veterans Administration Health Center, Atlanta, GA, USA
| | - Menghsiao Meng
- Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Road, 250, Taichung, Taiwan.
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
- Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
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12
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Constantin A, Constantin R, Achim F, Socea B, Predescu D. Pregnancy and Gastric Cancer: A Narrative Review. Diagnostics (Basel) 2023; 13:diagnostics13111909. [PMID: 37296761 DOI: 10.3390/diagnostics13111909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Cases of digestive cancers diagnosed during pregnancy are rare. The increasing prevalence of pregnancy in women aged 30-39 years (and not exceptionally 40-49 years) could explain the frequent co-occurrence of cancers and pregnancy. The diagnosis of digestive cancers in pregnancy is difficult due to the overlap between neoplasm symptomatology and the clinical picture of pregnancy. A paraclinical evaluation may also be difficult depending on the trimester of the pregnancy. Diagnosis is also delayed by practitioners' hesitation to use invasive investigations (imaging, endoscopy, etc.) due to fetal safety concerns. Therefore, digestive cancers are often diagnosed during pregnancy in advanced stages, where complications such as occlusions, perforations, and cachexia have already arisen. In this review, we highlight the epidemiology, clinical aspects, paraclinical evaluation, and particularities of the diagnosis and treatment of gastric cancer during pregnancy.
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Affiliation(s)
- Adrian Constantin
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Roxana Constantin
- Department of Obstetrics and Gynecology, Sanador Hospital, 010991 Bucharest, Romania
| | - Florin Achim
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Bogdan Socea
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
- Department of Surgery, Sf. Pantelimon Emergency Clinical Hospital, 021659 Bucharest, Romania
| | - Dragos Predescu
- Department of Esophageal and General Surgery, Sf. Maria Clinical Hospital Bucharest, 011192 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
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13
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Ogata T, Narita Y, Wainberg ZA, Van Cutsem E, Yamaguchi K, Piao Y, Zhao Y, Peterson PM, Wijayawardana SR, Abada P, Chatterjee A, Muro K. Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study. J Gastric Cancer 2023; 23:289-302. [PMID: 37129153 PMCID: PMC10154140 DOI: 10.5230/jgc.2023.23.e15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 12/19/2022] [Accepted: 12/25/2022] [Indexed: 05/03/2023] Open
Abstract
PURPOSE Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01170663.
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Affiliation(s)
| | | | - Zev A Wainberg
- University of California Los Angeles, Los Angeles, CA, United States
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg/Leuven & Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Kensei Yamaguchi
- Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | - Yumin Zhao
- Eli Lilly and Company, Indianapolis, IN, United States
| | | | | | - Paolo Abada
- Eli Lilly and Company, Indianapolis, IN, United States
| | | | - Kei Muro
- Aichi Cancer Center Hospital, Nagoya, Japan.
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14
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Wan Z, Wang Y, Li A, Li C, Zheng D. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma. Open Life Sci 2023; 18:20220569. [PMID: 36816799 PMCID: PMC9922059 DOI: 10.1515/biol-2022-0569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/25/2022] [Accepted: 01/14/2023] [Indexed: 02/11/2023] Open
Abstract
Bilateral renal clear cell carcinoma (BRCC) is a rare type of renal cell carcinoma (RCC) that accounts for only 1-5% of RCC cases and has a poor clinical prognosis. The origin, tumor microenvironment, cellular molecular features, and intra-tumoral heterogeneity of BRCC are still unclear. We downloaded BRCC single-cell transcriptome sequencing data from the gene expression omnibus database biochip GSE171306, containing 3,575 cells from left-sided clear cell renal cell carcinoma (ccRCC) and 3,568 cells from right-sided ccRCC, and used a series of R packages for data quality control (QC) and subsequent analysis of BRCC single-cell transcriptome data, including the use of the R packages Seurat and scCancer for cell QC, identification of major cell types, and cell annotation; R package scran for calculation of cell cycle scores; R package infercnv for malignancy scoring of tumor cells; R package ReactomeGSA for functional enrichment analysis; R package Monocle 2 for the analysis of cell differentiation trajectories; and R package CellphoneDB for the analysis of intercellular interactions. In this study, by analyzing the high-quality single-cell transcriptome data of BRCC, we identified 18 cell types and found that left- and right-sided ccRCC were approximately the same in terms of cell type and the number of each cell but differed significantly in terms of tumor cell malignancy score, tumor microenvironment, and cell stemness score. In the cell differentiation trajectory analysis of BRCC, we found that endothelial cells and macrophages play an extremely important role in its tumor progression. Further cell communication analysis was performed, and we found that it may signal through ligand-receptors, such as vascular endothelial growth factor-vascular endothelial growth factor receptor1 (VEGF-VEGFR1), MIF-(CD74-CXCR4), and growth arrest-specific protein 6-AXL, to influence the development of BRCC. The analysis of single-cell transcriptomic data of human BRCC suggests that left- and right-sided ccRCC may be of the same tumor origin, but the left-sided ccRCC is more malignant and has a better immune response.
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Affiliation(s)
- Zhengqiang Wan
- The Second Clinical Medical College of Binzhou Medical University, Shandong, China
| | - Yinglei Wang
- The Second Ward of Urology, Yantai Affiliated Hospital of Binzhou Medical University, Shandong, China
| | - Aiqun Li
- Emergency Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Shandong, China
| | - Cheng Li
- The Second Clinical Medical College of Binzhou Medical University, Shandong, China
| | - Dongbing Zheng
- The Second Ward of Urology, Yantai Affiliated Hospital of Binzhou Medical University, Shandong, China
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15
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Stroes CI, Schokker S, Khurshed M, van der Woude SO, Mathôt RA, Slingerland M, de Vos-Geelen J, Zucchetti M, Matteo C, van Dijk E, Ylstra B, Thijssen V, Derks S, Godefa T, Dijksterhuis W, Breimer GE, van Delden OM, Verhoeven RH, Meijer SL, Bijlsma MF, van Laarhoven HW. A phase Ib/II study of regorafenib and paclitaxel in patients with beyond first-line advanced esophagogastric carcinoma (REPEAT). Ther Adv Med Oncol 2022; 14:17588359221109196. [PMID: 35782751 PMCID: PMC9244942 DOI: 10.1177/17588359221109196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 06/06/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose: Regorafenib monotherapy, a multikinase inhibitor of angiogenesis, tumor microenvironment, and tumorigenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in patients with advanced esophagogastric cancer (EGC) refractory to first-line treatment, and explore potential biomarkers. Methods: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on days 1–21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall survival (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second-/third-line systemic treatment. Paclitaxel pharmacokinetics were assessed using samples from day 1 (D1) and day 15 (D15). We performed enzyme-linked immunosorbent assay measurements of galectin-1, RNA sequencing, and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. Results: In the dose-escalation cohort (n = 14), the MTD of regorafenib was 120 mg. In all, 34 patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ⩾ 3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up: 7.8 months). OS (p = 0.08) and PFS (p = 0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p < 0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p < 0.01). Enrichment of angiogenesis-related gene expression was observed in short survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p = 0.02) and PFS (p = 0.02). Conclusion: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response. Registration: Clinicaltrials.gov, NCT02406170, https://clinicaltrials.gov/ct2/show/NCT02406170
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Affiliation(s)
- Charlotte I Stroes
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands
| | - Sandor Schokker
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Mohammed Khurshed
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Stephanie O van der Woude
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Ron Aa Mathôt
- Department of Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marije Slingerland
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Judith de Vos-Geelen
- Department of Internal Medicine, Division of Medical Oncology, GROW-School for Oncology and Development Biology, Maastricht UMC+, Maastricht, The Netherlands
| | - Massimo Zucchetti
- Department of Oncology, Laboratory of Cancer Pharmacology, Istituto di Ricerche Farmacologice Mario Negri IRCCS, Milan, Italy
| | - Cristina Matteo
- Department of Oncology, Laboratory of Cancer Pharmacology, Istituto di Ricerche Farmacologice Mario Negri IRCCS, Milan, Italy
| | - Erik van Dijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Bauke Ylstra
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Victor Thijssen
- Department of Radiation Oncology, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Sarah Derks
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Tesfay Godefa
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Willemieke Dijksterhuis
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Gerben E Breimer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Otto M van Delden
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Rob Ha Verhoeven
- Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands
| | - Sybren L Meijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Maarten F Bijlsma
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Hanneke Wm van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands
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16
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Kasai S, Kuwayama N, Motoo Y, Kawashima A, Matsumoto K, Yano S, Matsushima K, Yasumoto K. Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer. Biochem Biophys Res Commun 2022; 600:80-86. [DOI: 10.1016/j.bbrc.2022.02.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 12/15/2022]
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17
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Serrano VB, Montoya JL, Campbell LM, Sundermann EE, Iudicello J, Letendre S, Heaton RK, Moore DJ. The relationship between vascular endothelial growth factor (VEGF) and amnestic mild cognitive impairment among older adults living with HIV. J Neurovirol 2021; 27:885-894. [PMID: 34735690 PMCID: PMC8901513 DOI: 10.1007/s13365-021-01001-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/03/2021] [Accepted: 07/13/2021] [Indexed: 10/27/2022]
Abstract
Older people with HIV (PWH) experience increased risk of age-related neurodegenerative disorders and cognitive decline, such as amnestic mild cognitive impairment (aMCI). The objective of this study was to examine the relationship between aMCI and plasma VEGF biomarkers among older PWH. Data were collected at a university-based research center from 2011 to 2013. Participants were 67 antiretroviral therapy-treated, virally suppressed PWH. Participants completed comprehensive neurobehavioral and neuromedical evaluations. aMCI status was determined using adapted Jak/Bondi criteria, classifying participants as aMCI + if their performance was > 1 SD below the normative mean on at least two of four memory assessments. VEGF family plasma biomarkers (i.e., VEGF, VEGF-C, VEGF-D, and PIGF) were measured by immunoassay. Logistic regression models were conducted to determine whether VEGF biomarkers were associated with aMCI status. Participants were mostly non-Hispanic white (79%) men (85%) with a mean age of 57.7 years. Eighteen (26.9%) participants met criteria for aMCI. Among potential covariates, only antidepressant drug use differed by aMCI status, and was included as a covariate. VEGF-D was significantly lower in the aMCI + group compared to the aMCI - group. No other VEGF levels (VEGF, VEGF-C, PIGF) differed by aMCI classification (ps > .05). In a sample of antiretroviral therapy-treated, virally suppressed PWH, lower levels of VEGF-D were associated with aMCI status. Longitudinal analyses in a larger and more diverse sample are needed to support VEGF-D as a putative biological marker of aMCI in HIV.
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Affiliation(s)
- Vanessa B Serrano
- Joint Doctoral Program in Clinical Psychology, San Diego State University, University of California, San Diego, La Jolla, CA, USA
| | - Jessica L Montoya
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Laura M Campbell
- Joint Doctoral Program in Clinical Psychology, San Diego State University, University of California, San Diego, La Jolla, CA, USA
| | - Erin E Sundermann
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Jennifer Iudicello
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Scott Letendre
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Robert K Heaton
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - David J Moore
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
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18
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Basile D, Simionato F, Cappetta A, Garattini SK, Roviello G, Aprile G. State-of-the-Art of Monoclonal Antibodies for the Treatment of Gastric Cancer. Biologics 2021; 15:451-462. [PMID: 34764633 PMCID: PMC8572727 DOI: 10.2147/btt.s290323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 10/05/2021] [Indexed: 12/07/2022]
Abstract
Gastric cancer (GC) is a complex and heterogeneous disease with poor prognosis and limited available treatment options. During recent years, several molecular stratifications have been proposed to optimize the overall treatment strategy for GC patients. Breakthroughs in cancer biology and in molecular profiling through DNA and RNA sequencing are now opening novel landscapes, leading to the personalization of molecular matched therapy. In particular, therapies against HER2, Claudine 18.2, Fibroblast Growth Factor Receptors (FGFR), and other molecular alterations could significantly improve survival outcomes in the advance phase of the disease. Furthermore, immunotherapy with checkpoint inhibitors also represents a promising option in a selected population. Hoping that precision oncology will enter soon in clinical practice, our review describes the state of the art of many novel pathways and the current evidence supporting the use of monoclonal antibodies implicated in GC treatment.
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Affiliation(s)
- Debora Basile
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
| | - Alessandro Cappetta
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
| | | | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Firenze, Firenze, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
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19
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Mustapha R, Ng K, Monypenny J, Ng T. Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis. Front Mol Biosci 2021; 8:661516. [PMID: 34568423 PMCID: PMC8455920 DOI: 10.3389/fmolb.2021.661516] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics.
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Affiliation(s)
- Rami Mustapha
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, United Kingdom
- Cancer Research UK King’s Health Partners Centre, London, United Kingdom
| | - Kenrick Ng
- UCL Cancer Institute, University College London, London, United Kingdom
- Department of Medical Oncology, University College Hospitals NHS Foundation Trust, London, United Kingdom
| | - James Monypenny
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, United Kingdom
| | - Tony Ng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, United Kingdom
- Cancer Research UK King’s Health Partners Centre, London, United Kingdom
- UCL Cancer Institute, University College London, London, United Kingdom
- Cancer Research UK City of London Centre, London, United Kingdom
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20
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Reddavid R, Dagatti S, Franco C, Puca L, Tomatis M, Corso S, Giordano S, Degiuli M. Molecularly Targeted Therapies for Gastric Cancer. State of the Art. Cancers (Basel) 2021; 13:4094. [PMID: 34439248 PMCID: PMC8392056 DOI: 10.3390/cancers13164094] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/26/2022] Open
Abstract
Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number.
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Affiliation(s)
- Rossella Reddavid
- Department of Oncology, Università degli Studi di Torino, 10126 Torino, Italy; (R.R.); (S.D.); (C.F.); (L.P.); (M.T.)
- Surgical Oncology and Digestive Surgery Unit, San Luigi University Hospital, Regione Gonzole 10, Orbassano, 10043 Turin, Italy
| | - Simona Dagatti
- Department of Oncology, Università degli Studi di Torino, 10126 Torino, Italy; (R.R.); (S.D.); (C.F.); (L.P.); (M.T.)
- Surgical Oncology and Digestive Surgery Unit, San Luigi University Hospital, Regione Gonzole 10, Orbassano, 10043 Turin, Italy
| | - Caterina Franco
- Department of Oncology, Università degli Studi di Torino, 10126 Torino, Italy; (R.R.); (S.D.); (C.F.); (L.P.); (M.T.)
- Surgical Oncology and Digestive Surgery Unit, San Luigi University Hospital, Regione Gonzole 10, Orbassano, 10043 Turin, Italy
| | - Lucia Puca
- Department of Oncology, Università degli Studi di Torino, 10126 Torino, Italy; (R.R.); (S.D.); (C.F.); (L.P.); (M.T.)
- Surgical Oncology and Digestive Surgery Unit, San Luigi University Hospital, Regione Gonzole 10, Orbassano, 10043 Turin, Italy
| | - Mariano Tomatis
- Department of Oncology, Università degli Studi di Torino, 10126 Torino, Italy; (R.R.); (S.D.); (C.F.); (L.P.); (M.T.)
- Surgical Oncology and Digestive Surgery Unit, San Luigi University Hospital, Regione Gonzole 10, Orbassano, 10043 Turin, Italy
| | - Simona Corso
- Department of Oncology, University of Torino, 10060 Candiolo, Italy; (S.C.); (S.G.)
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo, 10060 Turin, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, 10060 Candiolo, Italy; (S.C.); (S.G.)
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo, 10060 Turin, Italy
| | - Maurizio Degiuli
- Department of Oncology, Università degli Studi di Torino, 10126 Torino, Italy; (R.R.); (S.D.); (C.F.); (L.P.); (M.T.)
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21
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Razavi ZS, Asgarpour K, Mahjoubin-Tehran M, Rasouli S, Khan H, Shahrzad MK, Hamblin MR, Mirzaei H. Angiogenesis-related non-coding RNAs and gastrointestinal cancer. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:220-241. [PMID: 34095461 PMCID: PMC8141508 DOI: 10.1016/j.omto.2021.04.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal (GI) cancers are among the main reasons for cancer death globally. The deadliest types of GI cancer include colon, stomach, and liver cancers. Multiple lines of evidence have shown that angiogenesis has a key role in the growth and metastasis of all GI tumors. Abnormal angiogenesis also has a critical role in many non-malignant diseases. Therefore, angiogenesis is considered to be an important target for improved cancer treatment. Despite much research, the mechanisms governing angiogenesis are not completely understood. Recently, it has been shown that angiogenesis-related non-coding RNAs (ncRNAs) could affect the development of angiogenesis in cancer cells and tumors. The broad family of ncRNAs, which include long non-coding RNAs, microRNAs, and circular RNAs, are related to the development, promotion, and metastasis of GI cancers, especially in angiogenesis. This review discusses the role of ncRNAs in mediating angiogenesis in various types of GI cancers and looks forward to the introduction of mimetics and antagonists as possible therapeutic agents.
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Affiliation(s)
| | - Kasra Asgarpour
- Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Susan Rasouli
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Mohammad Karim Shahrzad
- Department of Internal Medicine and Endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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22
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Zhang JY, Xue WJ, Wang M, Li W, Dong R, Li MT, Sun LP. Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors. Chem Biodivers 2021; 18:e2100095. [PMID: 33829649 DOI: 10.1002/cbdv.202100095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/06/2021] [Indexed: 11/08/2022]
Abstract
Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 μM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.
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Affiliation(s)
- Jin-Yang Zhang
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Wen-Jun Xue
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Min Wang
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Wen Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Ru Dong
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Ming-Tao Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Li-Ping Sun
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
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Abstract
OPINION STATEMENT Despite a decreasing incidence in the USA, gastric cancer is highly prevalent worldwide. Furthermore, gastric cancer remains highly lethal with median survival of less than 1 year for metastatic disease. The backbone of therapy against metastatic gastric cancer remains cytotoxic chemotherapy, but recent advances in the molecular understanding of gastric cancer have renewed hope within that targeted agents can be leveraged to improve survival and reduce toxicity. For example, in patients with human epidermal growth factor-2 (HER2)-positive gastric cancer, the addition of trastuzumab to frontline chemotherapy improves survival. In the second line, oncologists can now administer a vascular endothelial growth factor (VEGF) receptor inhibitor, ramucirumab, as a single agent or in combination with chemotherapy, and the immune checkpoint inhibitor pembrolizumab is approved in multiple settings dependent on the Programmed Death Ligand 1 (PD-L1) status. For patients with metastatic disease, our approach to standard of care in the first-line setting is a 5FU/platinum doublet with trastuzumab for HER2-positive tumors. In the second-line setting, most patients receive ramucirumab + paclitaxel, but those that are MSI high receive pembrolizumab. For squamous cell carcinoma of the esophagus with high PD-L1 status (combined positive score (CPS) ≥ 10), we recommend pembrolizumab in the second line. While for PD-L1 ≥ 1% gastroesophageal adenocarcinoma, we do not recommend pembrolizumab before the third-line setting, although this may change in the near future for CPS ≥ 10. The future landscape for targeted therapy in gastric cancer is promising. Numerous clinical trials evaluating the combination immune therapy with molecularly targeted agents are generating much excitement. Moreover, genomic data from The Cancer Center Genome (TCGA) and Asian Cancer Research Group (ACRG) classifications is being used to identify molecular subtypes to enable future clinical trials to include biomarker-enriched patient populations.
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24
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Li S, Peng L, Tan C, Zeng X, Wan X, Luo X, Yi L, Li J. Cost-Effectiveness of ramucirumab plus paclitaxel as a second-line therapy for advanced gastric or gastro-oesophageal cancer in China. PLoS One 2020; 15:e0232240. [PMID: 32379763 PMCID: PMC7205241 DOI: 10.1371/journal.pone.0232240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 04/11/2020] [Indexed: 12/24/2022] Open
Abstract
AIM That clinical trial (RAINBOW) showed that a 7.4 months overall survival benefit with the combination therapy with ramucirumab (RAM) and paclitaxel (PAC) as second-line therapy for patients with recurrent or metastatic gastric or gastro-oesophageal junction adenocarcinoma, compared with placebo (PLA) plus paclitaxel. We performed an analysis to assess the cost-effectiveness of RAM from a Chinese perspective and recognized the range of drug costs. METHODS By building a Markov model to estimate quality-adjusted life-years (QALYs), life-years (LYs) and lifetime costs. Transition probabilities, costs and utilities were estimated for the published literature, Chinese health care system and local price setting. We performed threshold analyses and probabilistic sensitivity analyses to evaluate the uncertainty of the model. RESULTS Compared with PLA strategy, RAM strategy provided an incremental survival benefit of 1.22 LYs and 0.64 QALYs. The probabilistic sensitivity analysis showed that when RAM costs less than $151 or $753 per 4 weeks, the incremental cost-effectiveness ratio (ICER) approximated the willingness-to-pay threshold (WTP), suggesting that there was 50% likelihood that the ICER for RAM + PAC would be less than $44528.4 per QALY or $48121 per QALY, respectively. CONCLUSIONS For patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who fail first-line chemotherapy, our results are conducive to the multilateral drug price guidance negotiations of RAM in China.
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Affiliation(s)
- Sini Li
- The Xiangya Nursing School, Central South University, Changsha, Hunan, China
| | - Liubao Peng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chongqing Tan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaohui Zeng
- The Second Xiangya Hospital, PET-CT Center, Central South University, Changsha, Hunan, China
| | - Xiaomin Wan
- The Xiangya Nursing School, Central South University, Changsha, Hunan, China
| | - Xia Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lidan Yi
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianhe Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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25
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Oplawski M, Dziobek K, Zmarzły N, Grabarek B, Halski T, Januszyk P, Kuś-Kierach A, Adwent I, Dąbruś D, Kiełbasiński K, Boroń D. Expression Profile of VEGF-C, VEGF-D, and VEGFR-3 in Different Grades of Endometrial Cancer. Curr Pharm Biotechnol 2020; 20:1004-1010. [PMID: 31333122 DOI: 10.2174/1389201020666190718164431] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/22/2019] [Accepted: 07/08/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF)-C, -D, and VEGF receptor-3 are proteins characterized as crucial for tumor lymphangiogenesis. It is accompanied by angiogenesis during wound healing, but also in the neoplastic process. The research studies have shown that the lymphatic system plays a key role in the progression of carcinogenesis. OBJECTIVE The aim of this study was to evaluate changes in the expression of VEGF-C, VEGF-D and VEGFR-3 in different grades of endometrial cancer (G1-G3). METHODS The study included 45 patients diagnosed with endometrial cancer (G1=17; G2=15; G3=13) and 15 patients without neoplastic changes. The expression of VEGF-C, VEGF-D, and VEGFR-3 was assessed using microarray technique and immunohistochemistry. Statistical analysis was performed using the one-way ANOVA and Tukey's post-hoc test. RESULTS Statistically significant changes in the expression at the transcriptome level were found only in the case of VEGF-C (G1 vs. C, fold change - FC = -1.15; G2 vs. C, FC = -2.33; G3 vs. C, FC = - 1.68). However, VEGF-D and VEGFR-3 were expressed at the protein level. Analysis of VEGF-D expression showed that the optical density of the reaction product in G1 reached 101.7, while the values in G2 and G3 were 142.7 and 184.4, respectively. For VEGF-R3, the optical density of the reaction product reached the following levels: 72 in control, 118.77 in G1, 145.8 in G2, and 170.9 in G3. CONCLUSION An increase in VEGF-D and VEGFR-3 levels may indicate that VEGF-D-dependent processes are intensified along with the dedifferentiation of tumor cells. The lack of VEGF-C expression in endometrial cancer samples may suggest that this tumor is characterized by a different mechanism of metastasis than EMT. Our study emphasizes that when analyzing the metastatic potential of cancer, the expression of more than one factor should be taken into account.
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Affiliation(s)
- Marcin Oplawski
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Cracow, Poland
| | - Konrad Dziobek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Warsaw, Poland
| | - Nikola Zmarzły
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
| | - Beniamin Grabarek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Warsaw, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland
| | - Tomasz Halski
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Piotr Januszyk
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Cracow, Poland
| | - Agnieszka Kuś-Kierach
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Iwona Adwent
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Dariusz Dąbruś
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | | | - Dariusz Boroń
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Cracow, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
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26
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Cavaliere A, Merz V, Casalino S, Zecchetto C, Simionato F, Salt HL, Contarelli S, Santoro R, Melisi D. Novel Biomarkers for Prediction of Response to Preoperative Systemic Therapies in Gastric Cancer. J Gastric Cancer 2019; 19:375-392. [PMID: 31897341 PMCID: PMC6928085 DOI: 10.5230/jgc.2019.19.e39] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/02/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.
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Affiliation(s)
- Alessandro Cavaliere
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Valeria Merz
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Simona Casalino
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Camilla Zecchetto
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Francesca Simionato
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Hayley Louise Salt
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Raffaela Santoro
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Davide Melisi
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
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27
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Zhu G, Du Q, Chen X, Wang X, Tang N, She F, Chen Y. Receptor‑interacting serine/threonine‑protein kinase 1 promotes the progress and lymph metastasis of gallbladder cancer. Oncol Rep 2019; 42:2435-2449. [PMID: 31545498 PMCID: PMC6844244 DOI: 10.3892/or.2019.7331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 05/30/2019] [Indexed: 01/14/2023] Open
Abstract
Receptor-interacting serine/threonine-protein kinase 1 (RIP-1) is highly expressed in gallbladder cancer, and is very important in promoting tumor proliferation and invasion. The underlying mechanism in this promotion is the RIP-1-nuclear factor κ-B (NF-κB) and activator protein 1 (AP-1)-vascular endothelial growth factor-C (VEGF-C) signaling pathways. However, the precise mechanisms by which RIP-1 regulates VEGF-C expression are still unknown. The current study aims to clarify the detailed mechanisms by which RIP-1 upregulates VEGF-C expression. In the current study, the authors constructed various VEGF-C promoter deletions, VEGF-C promoter mutations and RIP-1 overexpression plasmids, and silenced RIP-1 with a small interfering RNA. Promoter analysis, an electrophoretic mobility shift assay, a chromatin immunoprecipitation assay was then performed, and an orthotopic transplantation model in nude mice was established by modified methods previously used. The authors also found that the core region for luciferase activity in the VEGF-C promoter was −332 to −190 nt, in which there are two overlapping AP-1 sites and an NF-κB site. RIP-1 was demonstrated to activate transcription factors NF-κB and AP-1 to combine with the core region and enhance VEGF-C promoter activity. In conclusion, the current study illustrated the mechanisms by which RIP-1 regulates VEGF-C expression, by activating NF-κB and AP-1 to combine with the −332 to −190 nt area of the VEGF-C promoter. By establishing an orthotopic mouse model of gallbladder cancer tumors, it was further elucidated that RIP-1 promotes gallbladder cancer metastasis. The findings provide evidence that targeting RIP-1 may prove to be useful in the treatment of gallbladder cancer.
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Affiliation(s)
- Guangwei Zhu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Qiang Du
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Xiao Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Xiaoqian Wang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Nanhong Tang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Feifei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer and Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yanling Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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Pak KH, Park KC, Cheong JH. VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC Cancer 2019; 19:799. [PMID: 31409309 PMCID: PMC6692962 DOI: 10.1186/s12885-019-5972-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 07/23/2019] [Indexed: 01/24/2023] Open
Abstract
Background The role of TGF-β1 in lymph node metastasis and lymphangiogenesis, one of the most important steps of gastric cancer dissemination, is largely unknown. The goal of this study was to investigate the role of TGF-β1 signaling and its molecular mechanisms involved in lymphangiogenesis of gastric cancer. Methods Two gastric cell line models, MKN45 and KATOIII, were selected for this study. The protein expression of TGF-β1 pathway molecules and VEGF-C were examined with western blot, or ELISA according to TGF-β1 treatment. To explore whether Smad3 binds to the specific DNA sequences in the VEGFC promoter, we performed an electrophoretic mobility shift assay. Lymphatic tube forming assay and gastric cancer xenograft mouse models were also used to elucidate the effect of TGF-β1 on lymphangiogenesis. Results TGF-β1 induced the activation of Smad2/3 and Smad pathway-modulated VEGF-C expression in gastric cancer cell line models. Phosphorylated and activated Smad3 in the nucleus bound to the promoter of VEGFC in KATO III cells. Of note, in MKN45 cells, the Smad-independent AKT pathway was also activated in response to TGF-β1 and induced VEGF-C expression. Inhibition of TGF-β1 signaling down-regulated the expression of VEGF-C. We also confirmed, through tube forming assay and tumor xenograft mouse model, that TGF-β1 increased lymphatic formation, while TGF-β1 inhibition blocked lymphangiogenesis. Conclusion Smad-dependent and -independent TGF-β1 pathways induce VEGF-C, which make lymphangiogenesis around tumor. These findings suggest that TGF-β might be a potential therapeutic target for preventing gastric cancer progression and dissemination. Electronic supplementary material The online version of this article (10.1186/s12885-019-5972-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kyung Ho Pak
- Department of Surgery, Hallym University Medical Center, Hwasung, Korea.,Department of Medicine, Yonsei University Graduate School, Seoul, Korea
| | - Ki Cheong Park
- Depatment of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Jae-Ho Cheong
- Depatment of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea. .,Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, Korea. .,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Jakubek M, Kejík Z, Kaplánek R, Hromádka R, Šandriková V, Sýkora D, Antonyová V, Urban M, Dytrych P, Mikula I, Martásek P, Král V. Strategy for improved therapeutic efficiency of curcumin in the treatment of gastric cancer. Biomed Pharmacother 2019; 118:109278. [PMID: 31387004 DOI: 10.1016/j.biopha.2019.109278] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer is a common oncological disease. Although enormous efforts have been expended, possible therapeutic modalities are still limited. For this reason, new therapeutic approaches and agents are highly requested and intensively developed. One strategy is the application of natural agents, such as curcumin, with proven anticancer effects and low toxicity for patients. Therefore, this review discusses the potential application of curcumin in the therapy of gastric cancer and its potential incorporation in therapeutic regimens. Because one of the largest impediments for widespread curcumin application is its limited bioavailability (caused mainly by its very low water solubility), studied strategies (drug delivery systems and curcumin derivatization) aimed to solve this obstacle are discussed in more detail.
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Affiliation(s)
- Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic.
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic
| | - Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
| | - Róbert Hromádka
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Research and Development Center C2P s.r.o., Jungmannova 101, 503 51 Chlumec nad Cidlinou, Czech Republic
| | - Viera Šandriková
- Research and Development Center C2P s.r.o., Jungmannova 101, 503 51 Chlumec nad Cidlinou, Czech Republic
| | - David Sýkora
- Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
| | - Veronika Antonyová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic
| | - Marian Urban
- Food Research Institute Prague, Radiová 1285/7, 1285/7, Prague 10, Czech Republic
| | - Petr Dytrych
- 1st Department of Surgery - Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08 Prague 2, Czech Republic
| | - Ivan Mikula
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
| | - Pavel Martásek
- Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic
| | - Vladimír Král
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 121 00 Prague 2, Czech Republic; Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
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30
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Monteiro AC, Muenzner JK, Andrade F, Rius FE, Ostalecki C, Geppert CI, Agaimy A, Hartmann A, Fujita A, Schneider-Stock R, Jasiulionis MG. Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma. Mol Oncol 2019; 13:1433-1449. [PMID: 31069961 PMCID: PMC6547615 DOI: 10.1002/1878-0261.12501] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/18/2019] [Accepted: 05/08/2019] [Indexed: 01/06/2023] Open
Abstract
The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P‐value = 0.044) and the lymphangiogenic receptor VEGFR‐3 (P‐value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing‐based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P‐value = 0.031), ANGPT2 (P‐value < 0.001), and SIX1 (P‐value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio‐ and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.
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Affiliation(s)
- Ana Carolina Monteiro
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.,Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Julienne K Muenzner
- Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Fernando Andrade
- Department of Computer Science, Institute of Mathematics and Statistics, Universidade de São Paulo, Brazil
| | - Flávia Eichemberger Rius
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil
| | - Christian Ostalecki
- Department of Dermatology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Germany
| | - Carol I Geppert
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - André Fujita
- Department of Computer Science, Institute of Mathematics and Statistics, Universidade de São Paulo, Brazil
| | - Regine Schneider-Stock
- Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
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Petrillo A, Laterza MM, Tirino G, Pompella L, Pappalardo A, Ventriglia J, Savastano B, Auricchio A, Orditura M, Ciardiello F, Galizia G, De Vita F. Increased circulating levels of vascular endothelial growth factor C can predict outcome in resectable gastric cancer patients. J Gastrointest Oncol 2019; 10:314-323. [PMID: 31032100 DOI: 10.21037/jgo.2018.12.06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background Neoangiogenesis has proven to be a relevant pathogenetic mechanism in gastric cancer (GC) and lymphatic spread represents an important well-known prognostic factor. Vascular endothelial growth factor C (VEGF-C) plays a key role in lymphangiogenesis and its blood levels in GC patients are easily measurable. This analysis aimed to investigate the prognostic role of preoperative VEGF-C blood levels. Methods VEGF-C serum levels were determined by enzyme-linked immunoadsorbent assay (ELISA) in 186 patients observed at our institution from January 2004 until December 2009 and 82 healthy subjects. Statistical analyses were performed using SPSS 21.0. Results VEGF-C levels were significantly higher in GC patients (median: 287.4 pg/mL; range, 76.2-865.2 pg/mL) than in the control group (median VEGF-C: 31 pg/mL; range, 12-97 pg/mL). A significant correlation between VEGF-C levels, T, N and tumor stage has been described. The median overall survival (OS) was statistically significantly higher in pts with low serum VEGF-C levels [median: not reached (NR) vs. 26 months; P<0.0001]. Higher preoperative VEGF-C levels correlated also with earlier disease relapse and poor disease-free survival (DFS) (median NR in each subgroup, P=0.005). Furthermore, high VEGF-C levels [hazard ratio (HR) =2.7; P=0.018] and tumor grading (HR =0.44; P=0.007) were independent prognostic factors for OS at multivariate analysis. Conclusions Our study showed that increased VEGF-C levels are significantly associated with advanced regional lymph node involvement and poor OS and DFS in pts with resected GC paving the way to a possible application as prognostic factor in the clinical practice.
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Affiliation(s)
- Angelica Petrillo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Maddalena Laterza
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Tirino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luca Pompella
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Annalisa Pappalardo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Jole Ventriglia
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Beatrice Savastano
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Annamaria Auricchio
- Division of GI Tract Surgical Oncology, Department of Cardio-Thoracic and Respiratory Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Orditura
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Gennaro Galizia
- Division of GI Tract Surgical Oncology, Department of Cardio-Thoracic and Respiratory Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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32
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Increased Expression of Vascular Endothelial Growth Factor-D Following Brain Injury. Int J Mol Sci 2019; 20:ijms20071594. [PMID: 30935023 PMCID: PMC6479775 DOI: 10.3390/ijms20071594] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 03/22/2019] [Accepted: 03/27/2019] [Indexed: 01/02/2023] Open
Abstract
Alterations in the expression of the vascular endothelial growth factors (VEGF) A and B occur during blood–brain barrier (BBB) breakdown and angiogenesis following brain injury. In this study, the temporal and spatial expression of VEGF-D and VEGF receptors-2 and -3 (VEGFR-2 and VEGFR-3, respectively) was determined at the mRNA and protein level in the rat cortical cold-injury model over a period of 0.5 to 6 days post-injury. In order to relate endothelial VEGF-D protein expression with BBB breakdown, dual labeling immunofluorescence was performed using antibodies to VEGF-D and to fibronectin, a marker of BBB breakdown. In control rats, VEGF-D signal was only observed in scattered perivascular macrophages in the cerebral cortex. The upregulation of VEGF-D mRNA expression was observed in the injury site between days 0.5 to 4, coinciding with the period of BBB breakdown and angiogenesis. At the protein level, intracerebral vessels with BBB breakdown to fibronectin in the lesion on days 0.5 to 4 failed to show endothelial VEGF-D. Between days 0.5 to 6, an increased VEGF-D immunoreactivity was noted in the endothelium of pial vessels overlying the lesion site, in neutrophils, macrophages, and free endothelial cells within the lesion. The upregulation of VEGFR-2 and -3 mRNA and protein expression was observed early post-injury on day 0.5. Although there was concurrent expression of VEGF-A, VEGF-B, and VEGF-D post-injury, differences in their spatial expression during BBB breakdown and angiogenesis suggest that they have specific and separate roles in these processes.
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33
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Shuto K, Mori M, Kosugi C, Narushima K, Nakabayashi S, Fujisiro T, Sato A, Hayano K, Shimizu H, Koda K. Hepatic blood flow by perfusion computed tomography as an imaging biomarker for patients with gastric cancer. Oncol Lett 2019; 17:3267-3276. [PMID: 30867759 PMCID: PMC6396202 DOI: 10.3892/ol.2019.9969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 01/17/2019] [Indexed: 11/19/2022] Open
Abstract
Perfusion computed tomography (PCT) is a less invasive imaging modality that provides information about tissue hemodynamics at the capillary level. The present study aimed to investigate the correlation between hepatic perfusion and gastric cancer progression. A total of 136 patients with gastric adenocarcinoma were evaluated in the present study. Prior to initial treatment, liver PCT was performed across the hepatic hilar plane and the hepatic blood flow (HBF) was measured using the dual-input deconvolution method. HBF was compared with clinicopathological factors, patient prognosis and circulating serum proangiogenic cytokines. The median HBF was 217 ml/min/100 g tissue. Patients with high HBF had larger tumors (43 mm vs. 71, P<0.001) and more advanced tumor-node stages (P<0.001 for both). When both patient groups of operable and inoperable were compared by their respective median HBF values, each high-HBF group had a significantly worse prognosis (P=0.002 and P=0.024), notably in the inoperable group, with <1-year survival. In 17 postoperative recurrent patients, the high-HBF at recurrence group also had a significantly worse postrecurrent prognosis (P=0.019). HBF was an independent prognostic factor (hazard ratio, 2.019; P=0.048) and was strongly associated with serum vascular endothelial growth factor level (R=0.607, P<0.001). HBF was significantly correlated with gastric cancer progression, and is an easily measured imaging biomarker reflecting patient survival.
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Affiliation(s)
- Kiyohiko Shuto
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Mikito Mori
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Chihiro Kosugi
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Kazuo Narushima
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Satoko Nakabayashi
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
| | - Takeshi Fujisiro
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Asami Sato
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiroaki Shimizu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan
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Loss of Multimerin-2 and EMILIN-2 Expression in Gastric Cancer Associate with Altered Angiogenesis. Int J Mol Sci 2018; 19:ijms19123983. [PMID: 30544909 PMCID: PMC6321373 DOI: 10.3390/ijms19123983] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 12/06/2018] [Indexed: 01/25/2023] Open
Abstract
Gastric cancer is a deadly tumor and a relatively common disease worldwide. Surgical resection and chemotherapy are the main clinical options to treat this type of disease, however the median overall survival rate is limited to one year. Thus, the development of new therapies is a highly necessary clinical need. Angiogenesis is a promising target for this tumor type, however clinical trials with the use of anti-angiogenic drugs have so far not met expectations. Therefore, it is important to better characterize the expression of molecules whose expression levels may impact on the efficacy of the treatments. In this study the characteristics of the gastric tumor associated blood vessels were first assessed by endomicroscopy. Next, we analyzed the expression of Multimerin-2, EMILIN-2 and EMILIN-1, three molecules of the EMI Domain ENdowed (EDEN) protein family. These molecules play important functions in the tumor microenvironment, affecting cancer progression both directly and indirectly impinging on angiogenesis and lymphangiogenesis. All the molecules were highly expressed in the normal mucosa whereas in a number of patients their expression was altered. We consider that better characterizing the gastric tumor microenvironment and the quality of the vasculature may achieve effective patient tailored therapies.
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35
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Holmström TH, Moilanen AM, Ikonen T, Björkman ML, Linnanen T, Wohlfahrt G, Karlsson S, Oksala R, Korjamo T, Samajdar S, Rajagopalan S, Chelur S, Narayanan K, Ramachandra RK, Mani J, Nair R, Gowda N, Anthony T, Dhodheri S, Mukherjee S, Ujjinamatada RK, Srinivas N, Ramachandra M, Kallio PJ. ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity. Mol Cancer Ther 2018; 18:28-38. [PMID: 30301864 DOI: 10.1158/1535-7163.mct-18-0204] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 08/20/2018] [Accepted: 10/04/2018] [Indexed: 11/16/2022]
Abstract
Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Jiju Mani
- Aurigene Discovery Technologies Limited, India
| | - Rashmi Nair
- Aurigene Discovery Technologies Limited, India
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Jung M, Ryu MH, Oh DY, Kang M, Zang DY, Hwang IG, Lee KW, Kim KH, Shim BY, Song EK, Sym SJ, Han HS, Park YL, Kim JS, Lee HW, Lee MH, Koo DH, Song HS, Lee N, Yang SH, Choi DR, Hong YS, Lee KE, Maeng CH, Baek JH, Kim S, Kim YH, Rha SY, Cho JY, Kang YK. Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG). Gastric Cancer 2018; 21:819-830. [PMID: 29427038 DOI: 10.1007/s10120-018-0806-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/30/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.
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Affiliation(s)
- Minkyu Jung
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-gu, Seoul, South Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Do Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Myounghee Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Jinju, South Korea
| | - Dae Young Zang
- Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, South Korea
| | - In Gyu Hwang
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Ki Hyang Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, South Korea
| | - Byoung Yong Shim
- Department of Medical Oncology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea
| | - Eun Kee Song
- Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, South Korea
| | - Sun Jin Sym
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea
| | - Young Lee Park
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, South Korea
| | - Jin Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Hyun Woo Lee
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, South Korea
| | - Moon Hee Lee
- Division of Hematology-Oncology, Inha University Hospital and College of Medicine, Incheon, South Korea
| | - Dong-Hoe Koo
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hong Suk Song
- Department of Internal Medicine, Dongsan Medical Center, Keimyung University, Daegu, South Korea
| | - Namsu Lee
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, South Korea
| | - Sung Hyun Yang
- Division of Hematology and Oncology, Department of Internal Medicine, Korea Cancer Center Hospital Korea, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Dae Ro Choi
- Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Chuncheon, South Korea
| | - Young Seon Hong
- Division of Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Kyoung Eun Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, South Korea
| | - Chi Hoon Maeng
- Division of Hematology-Oncology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, South Korea
| | - Jin Ho Baek
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Samyong Kim
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Yeul Hong Kim
- Department of Internal Medicine, Anam Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-gu, Seoul, South Korea.
| | - Jae Yong Cho
- Division of Medical Oncology, Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul, 06237, South Korea.
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Vassilakopoulou M, Harada K, Ajani JA. Ramucirumab for the treatment of gastric adenocarcinoma. Expert Opin Orphan Drugs 2018. [DOI: 10.1080/21678707.2018.1500689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Maria Vassilakopoulou
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Hematology and Medical Oncology, Group Hospitalier Sud Ile de France, Melun, France
| | - Kazuto Harada
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Gkolfinopoulos S, Papamichael D, Papadimitriou K, Papanastasopoulos P, Vassiliou V, Kountourakis P. Advances in molecular, genetic and immune signatures of gastric cancer: Are we ready to apply them in our patients' decision making? World J Gastrointest Oncol 2018; 10:172-183. [PMID: 30079143 PMCID: PMC6068857 DOI: 10.4251/wjgo.v10.i7.172] [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] [Received: 03/28/2018] [Revised: 05/16/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
In the last few years we have witnessed a vast expansion of our knowledge regarding the molecular and genetic profile of gastric cancer. The molecular subtypes described have shed light on the pathogenesis of the disease, thus prompting the development of new therapeutic strategies and favoring a more individualized approach for treatment. Most of the clinical trials for so called targeted therapies could be considered, at best, partially successful. In addition, checkpoint inhibitors have recently been added to our armamentarium in later stages of the disease, and combinations with chemotherapy and targeted agents are currently under development. In view of the rapid advances of molecular oncology, a new challenge for the clinical oncologist arises: The appropriate patient selection for each new therapy, which can be made possible only through the implementation of predictive biomarkers in our therapy decision making.
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Sakima M, Hayashi H, Mamun AA, Sato M. VEGFR-3 signaling is regulated by a G-protein activator, activator of G-protein signaling 8, in lymphatic endothelial cells. Exp Cell Res 2018; 368:13-23. [DOI: 10.1016/j.yexcr.2018.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 04/04/2018] [Accepted: 04/06/2018] [Indexed: 12/15/2022]
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40
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Karim ME, Tha KK, Othman I, Borhan Uddin M, Chowdhury EH. Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers. Pharmaceutics 2018; 10:E65. [PMID: 29861465 PMCID: PMC6026921 DOI: 10.3390/pharmaceutics10020065] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/19/2018] [Accepted: 05/22/2018] [Indexed: 02/07/2023] Open
Abstract
RNA Interference (RNAi) has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made to establish catalytic RNA as a new class of biologics for cancer management, a lot of extracellular and intracellular barriers still pose a long-lasting challenge on the way to clinical approval. A series of chemically suitable, safe and effective viral and non-viral carriers have emerged to overcome physiological barriers and ensure targeted delivery of RNAi. The newly invented carriers, delivery techniques and gene editing technology made current treatment protocols stronger to fight cancer. This review has provided a platform about the chronicle of siRNA development and challenges of RNAi therapeutics for laboratory to bedside translation focusing on recent advancement in siRNA delivery vehicles with their limitations. Furthermore, an overview of several animal model studies of siRNA- or shRNA-based cancer gene therapy over the past 15 years has been presented, highlighting the roles of genes in multiple cancers, pharmacokinetic parameters and critical evaluation. The review concludes with a future direction for the development of catalytic RNA vehicles and design strategies to make RNAi-based cancer gene therapy more promising to surmount cancer gene delivery challenges.
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Affiliation(s)
- Md Emranul Karim
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia.
| | - Kyi Kyi Tha
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia.
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia.
| | - Mohammad Borhan Uddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia.
| | - Ezharul Hoque Chowdhury
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia.
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41
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Soliman AM, Das S, Abd Ghafar N, Teoh SL. Role of MicroRNA in Proliferation Phase of Wound Healing. Front Genet 2018; 9:38. [PMID: 29491883 PMCID: PMC5817091 DOI: 10.3389/fgene.2018.00038] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/29/2018] [Indexed: 12/15/2022] Open
Abstract
Wound healing is a complex biological process that is generally composed of four phases: hemostasis, inflammation, proliferation, and remodeling. The proliferation phase is crucial for effective healing compared to other phases. Many critical events occur during this phase, i.e., migration of fibroblasts, re-epithelialization, angiogenesis and wound contraction. Chronic wounds are common and are considered a major public health problem. Therefore, there is the increasing need to discover new therapeutic strategies. MicroRNA (miRNA) research in the field of wound healing is in its early phase, but the knowledge of the recent discoveries is essential for developing effective therapies for the treatment of chronic wounds. In this review, we focused on recently discovered miRNAs which are involved in the proliferation phase of wound healing in the past few years and their role in wound healing.
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Affiliation(s)
| | | | | | - Seong Lin Teoh
- Department of Anatomy, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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42
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Emerging Roles for VEGF-D in Human Disease. Biomolecules 2018; 8:biom8010001. [PMID: 29300337 PMCID: PMC5871970 DOI: 10.3390/biom8010001] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/22/2017] [Accepted: 12/28/2017] [Indexed: 12/21/2022] Open
Abstract
Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling.
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43
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Xie M, Dart DA, Guo T, Xing XF, Cheng XJ, Du H, Jiang WG, Wen XZ, Ji JF. MicroRNA-1 acts as a tumor suppressor microRNA by inhibiting angiogenesis-related growth factors in human gastric cancer. Gastric Cancer 2018; 21:41-54. [PMID: 28493075 PMCID: PMC5741792 DOI: 10.1007/s10120-017-0721-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/17/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND We recently reported that miR-1 was one of the most significantly downregulated microRNAs in gastric cancer (GC) patients from The Cancer Genome Atlas microRNA sequencing data. Here we aim to elucidate the role of miR-1 in gastric carcinogenesis. METHODS We measured miR-1 expression in human GC cell lines and 90 paired primary GC samples, and analyzed the association of its status with clinicopathological features. The effect of miR-1 on GC cells was evaluated by proliferation and migration assay. To identify the target genes of miR-1, bioinformatic analysis and protein array analysis were performed. Moreover, the regulation mechanism of miR-1 with regard to these predicted targets was investigated by quantitative PCR (qPCR), Western blot, ELISA, and endothelial cell tube formation. The putative binding site of miR-1 on target genes was assessed by a reporter assay. RESULTS Expression of miR-1 was obviously decreased in GC cell lines and primary tissues. Patients with low miR-1 expression had significantly shorter overall survival compared with those with high miR-1 expression (P = 0.0027). Overexpression of miR-1 in GC cells inhibited proliferation, migration, and tube formation of endothelial cells by suppressing expression of vascular endothelial growth factor A (VEGF-A) and endothelin 1 (EDN1). Conversely, inhibition of miR-1 with use of antago-miR-1 caused an increase in expression of VEGF-A and EDN1 in nonmalignant GC cells or low-malignancy GC cells. CONCLUSIONS MiR-1 acts as a tumor suppressor by inhibiting angiogenesis-related growth factors in human gastric cancer. Downregulated miR-1 not only promotes cellular proliferation and migration of GC cells, but may activates proangiogenesis signaling and stimulates the proliferation and migration of endothelial cells, indicating the possibility of new strategies for GC therapy.
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Affiliation(s)
- Meng Xie
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Dafydd Alwyn Dart
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Ting Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiao-Fang Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiao-Jing Cheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hong Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China
| | - Wen G Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
| | - Xian-Zi Wen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Jia-Fu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China.
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Khanna P, Chua PJ, Wong BSE, Yin C, Thike AA, Wan WK, Tan PH, Baeg GH. GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis. Oncotarget 2017; 8:115370-115383. [PMID: 29383166 PMCID: PMC5777778 DOI: 10.18632/oncotarget.23265] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 12/03/2017] [Indexed: 12/31/2022] Open
Abstract
Dysregulated JAK/STAT signaling has been implicated in the molecular pathogenesis of gastric cancer. However, downstream effectors of STAT signaling that facilitate gastric carcinogenesis remain to be explored. We previously identified the Drosophila ortholog of human GRAMD1B in our genome-wide RNAi screen to identify novel components of the JAK/STAT signaling pathway in Drosophila. Here, we examined the involvement of GRAMD1B in JAK/STAT-associated gastric carcinogenesis. We found that GRAMD1B expression is positively regulated by JAK/STAT signaling and GRAMD1B inhibition decreases STAT3 levels, suggesting the existence of a positive feedback loop. Consistently, GRAMD1B and JAK/STAT signaling acted synergistically to promote gastric cancer cell survival by upregulating the expression of the anti-apoptotic molecule Bcl-xL. Interestingly, our immunohistochemical analysis for GRAMD1B revealed a gradual loss of cytoplasmic staining but an increase in the nuclear accumulation of GRAMD1B, as gastric tissue becomes malignant. GRAMD1B expression levels were also found to be significantly associated with clinicopathological features of the gastric cancer patients, particularly the tumor grades and lymph node status. Moreover, GRAMD1B and pSTAT3 (Tyr705) showed a positive correlation in gastric tissues, thereby confirming the existence of a close link between these two signaling molecules in vivo. This new knowledge about JAK/STAT-GRAMD1B regulation deepens our understanding of JAK/STAT signaling in gastric carcinogenesis and provides a foundation for the development of novel biomarkers in gastric cancer.
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Affiliation(s)
- Puja Khanna
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore
| | - Pei Jou Chua
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore
| | - Belinda Shu Ee Wong
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore
| | - Changhong Yin
- Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA
| | - Aye Aye Thike
- Division of Pathology, Singapore General Hospital, Singapore 169856, Singapore
| | - Wei Keat Wan
- Division of Pathology, Singapore General Hospital, Singapore 169856, Singapore.,Academic Clinical Program for Pathology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore
| | - Puay Hoon Tan
- Division of Pathology, Singapore General Hospital, Singapore 169856, Singapore
| | - Gyeong Hun Baeg
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore
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45
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Ge H, Yan Y, Guo L, He X, Yang X. Prognostic and clinical significance of VEGFR-3 in gastric cancer: A meta-analysis. Clin Chim Acta 2017; 474:114-119. [PMID: 28939099 DOI: 10.1016/j.cca.2017.09.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/17/2017] [Accepted: 09/18/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Recent studies have suggested that VEGFR-3 is involved in the development of gastric cancer, however, the results are contradictory. Hence, we conducted a meta-analysis to assess the correlation between VEGFR-3 and the clinicopathological characteristics of gastric cancer to assess its prognostic value. METHODS An electronic search for relevant articles was conducted in PubMed, Cochrane Library, Web of Science, EMBASE database, and Chinese CNKI. Correlations between VEGFR-3 expression and clinicopathological features and survival outcomes were analyzed. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. RESULTS Positive VEGFR-3 expression was not correlated with gender or tumor differentiation. However, high levels of VEGFR-3 expression were significantly associated with depth of invasion and lymph node metastasis. Moreover, VEGFR-3 expression was associated with poor three year and five year overall survival rates (OS) in GC patients. CONCLUSIONS Our meta-analysis found that VEGFR-3 expression was associated with depth of invasion and lymph node metastasis in gastric cancer. The results suggest that VEGFR-3 may be a useful prognostic biomarker for gastric cancer.
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Affiliation(s)
- Hua Ge
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China.
| | - Yan Yan
- Quality control department, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
| | - Lingfei Guo
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
| | - Xueyan He
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
| | - Xianzhi Yang
- Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, Zunyi Medical University, Zunyi, Guizhou, People's Republic of China
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Lubner SJ, Uboha NV, Deming DA. Primary and acquired resistance to biologic therapies in gastrointestinal cancers. J Gastrointest Oncol 2017; 8:499-512. [PMID: 28736637 PMCID: PMC5506279 DOI: 10.21037/jgo.2017.01.16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 11/09/2016] [Indexed: 12/11/2022] Open
Abstract
Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways.
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Affiliation(s)
- Sam J Lubner
- Department of Medicine, Hematology-Oncology Section, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
| | - Nataliya V Uboha
- Department of Medicine, Hematology-Oncology Section, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
| | - Dustin A Deming
- Department of Medicine, Hematology-Oncology Section, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
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Leong SH, Lwin KM, Lee SS, Ng WH, Ng KM, Tan SY, Ng BL, Carter NP, Tang C, Lian Kon O. Chromosomal breaks at FRA18C: association with reduced DOK6 expression, altered oncogenic signaling and increased gastric cancer survival. NPJ Precis Oncol 2017; 1:9. [PMID: 29872697 PMCID: PMC5859466 DOI: 10.1038/s41698-017-0012-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 02/16/2017] [Accepted: 02/21/2017] [Indexed: 12/13/2022] Open
Abstract
Chromosomal rearrangements are common in cancer. More than 50% occur in common fragile sites and disrupt tumor suppressors. However, such rearrangements are not known in gastric cancer. Here we report recurrent 18q2 breakpoints in 6 of 17 gastric cancer cell lines. The rearranged chromosome 18, t(9;18), in MKN7 cells was flow sorted and identified by reverse chromosome painting. High-resolution tiling array hybridization mapped breakpoints to DOK6 (docking protein 6) intron 4 in FRA18C (18q22.2) and an intergenic region in 9q22.2. The same rearrangement was detected by FISH in 22% of 99 primary gastric cancers. Intron 4 truncation was associated with reduced DOK6 transcription. Analysis of The Cancer Genome Atlas stomach adenocarcinoma cohort showed significant correlation of DOK6 expression with histological and molecular phenotypes. Multiple oncogenic signaling pathways (gastrin-CREB, NGF-neurotrophin, PDGF, EGFR, ERK, ERBB4, FGFR1, RAS, VEGFR2 and RAF/MAP kinase) known to be active in aggressive gastric cancers were strikingly diminished in gastric cancers with low DOK6 expression. Median survival of patients with low DOK6-expressing tumors was 2100 days compared with 533 days in patients with high DOK6-expressing tumors (log-rank P = 0.0027). The level of DOK6 expression in tumors predicted patient survival independent of TNM stage. These findings point to new functions of human DOK6 as an adaptor that interacts with diverse molecular components of signaling pathways. Our data suggest that DOK6 expression is an integrated biomarker of multiple oncogenic signals in gastric cancer and identify FRA18C as a new cancer-associated fragile site.
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Affiliation(s)
- Siew Hong Leong
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore.,2Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore, 117596 Singapore
| | - Kyaw Myo Lwin
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Sze Sing Lee
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Wai Har Ng
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Kia Min Ng
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Soo Yong Tan
- 3Department of Pathology, Singapore General Hospital, Outram Road, Singapore, 169608 Singapore
| | - Bee Ling Ng
- 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
| | - Nigel P Carter
- 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
| | - Carol Tang
- 5National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore
| | - Oi Lian Kon
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore.,2Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore, 117596 Singapore
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Liu X, Guo W, Zhang W, Yin J, Zhang J, Zhu X, Liu T, Chen Z, Wang B, Chang J, Lv F, Hong X, Wang H, Wang J, Zhao X, Wu X, Li J. A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer. BMC Cancer 2017; 17:188. [PMID: 28288572 PMCID: PMC5348753 DOI: 10.1186/s12885-017-3174-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 03/04/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes. METHODS All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/m2) thereafter, starting on day 1. On day 2 of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h. The primary endpoint was time-to-progression (TTP). RESULTS The response rate (RR) was 33.3% among 54 evaluable patients. In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 7.3-9.9 months). In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome. In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and 5 months, respectively (P <0.0001). None of these patients exhibited KRAS, BRAF, or PIK3CA mutations. CONCLUSIONS Combination therapy comprising cetuximab and mFOLFIRI was well tolerated and active as a second-line treatment for patients with metastatic gastric cancer. Patients with low baseline plasma VEGF levels were associated with better clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov. NCT00699881 . Registered 17 June 2008 (retrospectively registered).
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Affiliation(s)
- Xin Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Wen Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jiliang Yin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital of Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xiaodong Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Zhiyu Chen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Biyun Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Fangfang Lv
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xiaonan Hong
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Huijie Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jialei Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xinmin Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xianghua Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China.
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Apicella M, Corso S, Giordano S. Targeted therapies for gastric cancer: failures and hopes from clinical trials. Oncotarget 2017; 8:57654-57669. [PMID: 28915702 PMCID: PMC5593674 DOI: 10.18632/oncotarget.14825] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 01/17/2017] [Indexed: 12/25/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer mortality worldwide. As surgery is the only curative treatment strategy and conventional chemotherapy has shown limited efficacy -with a median overall survival of 10 months- new treatments are urgently needed. Trastuzumab and Ramucirumab (targeting HER2 and VEGFR2, respectively) are the only targeted therapies approved so far. Indeed, most Phase III clinical trials evaluating molecular drugs in gastric cancer failed. This review will retrace the relevant clinical trials with molecular therapies performed in gastric cancer patients, discussing the possible reasons for their failure and indicating new perspective for a real improvement of the treatment of this disease.
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Affiliation(s)
- Maria Apicella
- Department of Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy
| | - Simona Corso
- Department of Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy
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50
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Fuchs CS, Tabernero J, Tomášek J, Chau I, Melichar B, Safran H, Tehfe MA, Filip D, Topuzov E, Schlittler L, Udrea AA, Campbell W, Brincat S, Emig M, Melemed SA, Hozak RR, Ferry D, Caldwell CW, Ajani JA. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer 2016; 115:974-982. [PMID: 27623234 PMCID: PMC5061911 DOI: 10.1038/bjc.2016.293] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 08/12/2016] [Accepted: 08/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma. METHODS A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3. RESULTS None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression. CONCLUSIONS REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.
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Affiliation(s)
- Charles S Fuchs
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Jiří Tomášek
- Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno 656 53, Czech Republic
| | - Ian Chau
- Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
| | - Bohuslav Melichar
- Onkologicka klinika, Lekarska fakulta Univerzity Palackeho a Fakultni nemocnice, I.P. Pavlova, 6, Olomouc 779 00, Czech Republic
| | - Howard Safran
- Brown University Oncology Research Group, 164 Summit Avenue, Fain 3, Providence, Rhode Island 02906, USA
| | - Mustapha A Tehfe
- Centre Hospitalier de Montréal, 1560 Sherbrooke East St, Montreal, Quebec H2L4M1, Canada
| | - Dumitru Filip
- Spitalul Judetean de Urgenta, Strada George Coşbuc 31, Baia Mare 430031, Romania
| | - 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
| | - Luis Schlittler
- Hospital da Cida de Passo Fundo, Rua Tiradentes, 295 Centro, Passo Fundo, 99010-260, Brazil
| | | | | | | | - Michael Emig
- Lilly Deutschland GmbH, Werner-Reimers-Straße 2, Bad Homburg vor der Höhe 61352, Germany
| | - Symantha A Melemed
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - Rebecca R Hozak
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - David Ferry
- Eli Lilly and Company, 440 Route 22 East, Bridgewater, New Jersey 08807, USA
| | - C William Caldwell
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - Jaffer A Ajani
- The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, Texas 77030, USA
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