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1
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Cai J, Wang W, Cong D, Bai Y, Zhang W. Development of treatment strategies for advanced HER2-positive gastric cancer: Insights from clinical trials. Crit Rev Oncol Hematol 2025; 207:104617. [PMID: 39805409 DOI: 10.1016/j.critrevonc.2025.104617] [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: 04/05/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
HER2-positive gastric cancer (GC), a unique molecular subtype, has garnered significant interest in recent years. Here, we review clinical trial data on advanced HER2-positive GC from the past 15 years. Trastuzumab plus standard chemotherapy remain the first-line treatment. The initial survival benefits conferred by immune checkpoint inhibitors plus trastuzumab and standard chemotherapy are encouraging. The combination of ramucirumab and mono-chemotherapy, as well as the antibody conjugated drug trastuzumab deruxtecan, is the recommended second-line regimen. Treatment with immune checkpoint inhibitors plus ramucirumab and mono-chemotherapy shows promise. Despite the limited treatment options for third line and beyond, development of novel therapeutic strategies is expected. Although clinical cure of advanced HER2-positive GC is unlikely, current clinical studies offer valuable insight into regimens that prolong survival.
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Affiliation(s)
- Jing Cai
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wanning Wang
- Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China
| | - Dan Cong
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Yuansong Bai
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wenlong Zhang
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
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2
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Yun H, Dong F, Wei X, Yan X, Zhang R, Zhang X, Wang Y. Role and value of the tumor microenvironment in the progression and treatment resistance of gastric cancer (Review). Oncol Rep 2025; 53:14. [PMID: 39611496 PMCID: PMC11622107 DOI: 10.3892/or.2024.8847] [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: 08/08/2024] [Accepted: 10/08/2024] [Indexed: 11/30/2024] Open
Abstract
Gastric cancer (GC) is characterized by a complex and heterogeneous tumor microenvironment (TME) that significantly influences disease progression and treatment outcomes. The tumor stroma, which is composed of a variety of cell types such as cancer‑associated fibroblasts, immune cells and vascular components, displays significant spatial and temporal diversity. These stromal elements engage in dynamic crosstalk with cancer cells, shaping their proliferative, invasive and metastatic potential. Furthermore, the TME is instrumental in facilitating resistance to traditional chemotherapy, specific treatments and immunotherapy strategies. Understanding the underlying mechanisms by which the GC microenvironment evolves and supports tumor growth and therapeutic resistance is critical for developing effective treatment strategies. The present review explores the latest progress in understanding the intricate interactions between cancer cells and their immediate environment in GC, highlighting the implications for disease pathogenesis and therapeutic interventions.
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Affiliation(s)
- Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Fangde Dong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Xiaoqin Wei
- Department of Pain, The Second People's Hospital of Baiyin, Baiyin, Gansu 730900, P.R. China
| | - Xinyong Yan
- Department of Proctology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Ronglong Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Xiuyu Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
| | - Yulin Wang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, Gansu 730900, P.R. China
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3
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Saha S, Bapat S, Vijayasarathi D, Vyas R. Exploring potential biomarkers and lead molecules in gastric cancer by network biology, drug repurposing and virtual screening strategies. Mol Divers 2024:10.1007/s11030-024-10995-6. [PMID: 39348085 DOI: 10.1007/s11030-024-10995-6] [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: 07/10/2024] [Accepted: 09/15/2024] [Indexed: 10/01/2024]
Abstract
Gastric cancer poses a significant global health challenge, necessitating innovative approaches for biomarker discovery and therapeutic intervention. This study employs a multifaceted strategy integrating network biology, drug repurposing, and virtual screening to elucidate and expand the molecular landscape of gastric cancer. We identified and prioritized key genes implicated in gastric cancer by utilizing data from diverse databases and text-mining techniques. Network analysis underscored intricate gene interactions, emphasizing potential therapeutic targets such as CTNNB1, BCL2, TP53, etc, and highlighted ACTB among the top hub genes crucial in disease progression. Drug repurposing on 626 FDA-approved drugs for digestive system-related cancers revealed Norgestimate and Nimesulide as likely top candidates for gastric cancer, validated by molecular docking and dynamics simulations. Further, combinatorial synthesis of scaffold libraries derived from known chemotypes generated 56,160 virtual compounds, of which 76 new compounds were prioritized based on promising binding affinities and interactions at critical residues. Hotspot residue analysis identified GLU 214 and others as essential for ligand binding stability, enhancing compound efficacy and specificity. These findings support the therapeutic potential of targeting beta-actin protein in gastric cancer treatment, suggesting a future for further experimental validation and clinical translation. In conclusion, this study highlights the potential of repurposable drugs and virtual screening which can be used in combination with existing anti-gastric cancer drugs for gastric cancer therapy, emphasizing the role of computational methodologies in drug discovery.
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Affiliation(s)
- Sagarika Saha
- MIT ADTU School of Bioengineering Sciences & Research, MIT Art, Design and Technology University, Pune, Maharashtra, India
| | - Sanket Bapat
- MIT ADTU School of Bioengineering Sciences & Research, MIT Art, Design and Technology University, Pune, Maharashtra, India
| | - Durairaj Vijayasarathi
- MIT ADTU School of Bioengineering Sciences & Research, MIT Art, Design and Technology University, Pune, Maharashtra, India
| | - Renu Vyas
- MIT ADTU School of Bioengineering Sciences & Research, MIT Art, Design and Technology University, Pune, Maharashtra, India.
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4
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Sabatelle RC, Colson YL, Sachdeva U, Grinstaff MW. Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects. Mol Pharm 2024; 21:3103-3120. [PMID: 38888089 PMCID: PMC11331583 DOI: 10.1021/acs.molpharmaceut.4c00246] [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] [Indexed: 06/20/2024]
Abstract
With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.
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Affiliation(s)
- Robert C. Sabatelle
- Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, 02215, USA
| | - Yolonda L. Colson
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Uma Sachdeva
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Mark W. Grinstaff
- Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, 02215, USA
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Xu D, Luo Y, Wang P, Li J, Ma L, Huang J, Zhang H, Yang X, Li L, Zheng Y, Fang G, Yan P. Clinical progress of anti-angiogenic targeted therapy and combination therapy for gastric cancer. Front Oncol 2023; 13:1148131. [PMID: 37384288 PMCID: PMC10295723 DOI: 10.3389/fonc.2023.1148131] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 05/12/2023] [Indexed: 06/30/2023] Open
Abstract
The incidence of gastric cancer is increasing year by year. Most gastric cancers are already in the advanced stage with poor prognosis when diagnosed, which means the current treatment is not satisfactory. Angiogenesis is an important link in the occurrence and development of tumors, and there are multiple anti-angiogenesis targeted therapies. To comprehensively evaluate the efficacy and safety of anti-angiogenic targeted drugs alone and in combination against gastric cancer, we systematically searched and sorted out relevant literature. In this review, we summarized the efficacy and safety of Ramucirumab, Bevacizumab, Apatinib, Fruquintinib, Sorafenib, Sunitinib, Pazopanib on gastric cancer when used alone or in combination based on prospective clinical trials reported in the literature, and sorted response biomarkers. We also summarized the challenges faced by anti-angiogenesis therapy for gastric cancer and available solutions. Finally, the characteristics of the current clinical research are summarized and suggestions and prospects are raised. This review will serve as a good reference for the clinical research of anti-angiogenic targeted drugs in the treatment of gastric cancer.
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Affiliation(s)
- Donghan Xu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Yehao Luo
- School of Second Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peng Wang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Jiaxin Li
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Linrui Ma
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Jie Huang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Hao Zhang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Xiaoman Yang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Liqi Li
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Yuhong Zheng
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Gang Fang
- Guangxi Key Laboratory of Applied Fundamental Research of Zhuang Medicine, Guangxi University of Chinese Medicine, Nanning, China
| | - Peiyu Yan
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Macao, Macao SAR, China
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6
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Nakayama I, Takahari D. The Role of Angiogenesis Targeted Therapies in Metastatic Advanced Gastric Cancer: A Narrative Review. J Clin Med 2023; 12:jcm12093226. [PMID: 37176668 PMCID: PMC10178968 DOI: 10.3390/jcm12093226] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Since bevacizumab was first approved by the U.S. Food and Drug Administration as an anti-angiogenic therapy in 2004, angiogenesis-targeted therapy has been developed for various types of solid tumors. To date, ramucirumab and apatinib are clinically available as treatments for metastatic advanced gastric cancer (AGC). Ramucirumab demonstrated prolonged survival as second-line therapy of metastatic AGC in the RAINBOW and REGARD trials. However, neither ramucirumab extended survival in treatment-naïve patients with AGC in the RAINFALL or RAINSTORM trials nor bevacizumab in the AVAGAST and AVATAR trials. Apatinib demonstrated superior efficacy over the best supportive care in a Chinese phase III trial but not in an international phase III (ANGEL) trial. Currently, combination therapy of ramucirumab with irinotecan or FTD/TPI is being evaluated in the third-line setting, assessing the efficacy of continuous angiogenesis inhibition from second- to third-line therapy. Recently, the role of angiogenesis inhibition via immunomodulators is attractive to clinicians. Emerging results of several early-phase clinical trials indicated the promising antitumor activity of angiogenesis inhibition in combination with immune therapy. This review offers an overview of the history of clinical trials focused on anti-angiogenic for patients with AGC and presents future perspectives in this area.
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Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Daisuke Takahari
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
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7
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Zhang Y, Wang Z, Shen L, Li J, Huang J, Su W, Zhang D, Xu R. A phase Ib/II study of fruquintinib in combination with paclitaxel as the second-line therapy for advanced gastric cancer. Cancer Commun (Lond) 2023; 43:150-153. [PMID: 36331272 PMCID: PMC9859731 DOI: 10.1002/cac2.12379] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 09/02/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Yang Zhang
- Department of Clinical Research, Sun Yat‐Sen University Cancer Center, State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongChina
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal CancerChinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Zi‐Xian Wang
- Department of Medical OncologySun Yat‐Sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal CancerChinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Lin Shen
- Department of Gastrointestinal OncologyBeijing Cancer HospitalBeijingP. R. China
| | - Jin Li
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai Medical CollegeShanghaiP. R. China
| | - Jing Huang
- Department of Medical OncologyCancer Hospital Chinese Academy of Medical SciencesBeijingP. R. China
| | | | - Dong‐Sheng Zhang
- Department of Medical OncologySun Yat‐Sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal CancerChinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Rui‐Hua Xu
- Department of Medical OncologySun Yat‐Sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal CancerChinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
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8
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Haque E, Esmail A, Muhsen I, Salah H, Abdelrahim M. Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer. Cancers (Basel) 2022; 14:5615. [PMID: 36428707 PMCID: PMC9688354 DOI: 10.3390/cancers14225615] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is an enigmatic malignancy that has recently been shown to be increasing in incidence globally. There has been recent progress in emerging technologies for the diagnosis and treatment of the disease. Improvements in non-invasive diagnostic techniques with serological tests and biomarkers have led to decreased use of invasive procedures such as endoscopy. A multidisciplinary approach is used to treat gastric cancer, with recent significant advancements in systemic therapies used in combination with cytotoxic chemotherapies. New therapeutic targets have been identified and clinical trials are taking place to assess their efficacy and safety. In this review, we provide an overview of the current and emerging treatment strategies and diagnostic techniques for gastric cancer.
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Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
| | - Ibrahim Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Haneen Salah
- Department of Pathology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
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Salati M, Caputo F, Bocconi A, Cerri S, Baldessari C, Piacentini F, Dominici M, Gelsomino F. Successes and failures of angiogenesis blockade in gastric and gastro-esophageal junction adenocarcinoma. Front Oncol 2022; 12:993573. [PMID: 36212393 PMCID: PMC9540203 DOI: 10.3389/fonc.2022.993573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients' outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach.
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Affiliation(s)
- Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
- PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Alessandro Bocconi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Sara Cerri
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Cinzia Baldessari
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Federico Piacentini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
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10
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Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors. Bioorg Chem 2022; 128:106099. [PMID: 35994884 DOI: 10.1016/j.bioorg.2022.106099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/08/2022] [Accepted: 08/11/2022] [Indexed: 11/24/2022]
Abstract
The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC50 = 1.54 µM) relative to Lapatinib (IC50 = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC50 = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC50 = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC50 = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC50 = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC50 = 17.51 and 5.56 µM, respectively) and 14c (IC50 = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC50 = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.
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11
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Liu Y, Zhang J, Wang Z, Zhang X, Dai Z, Wu W, Zhang N, Liu Z, Zhang J, Luo P, Wen Z, Yu J, Zhang H, Yang T, Cheng Q. Identify the Prognostic and Immune Profile of VSIR in the Tumor Microenvironment: A Pan-Cancer Analysis. Front Cell Dev Biol 2022; 10:821649. [PMID: 35493077 PMCID: PMC9039624 DOI: 10.3389/fcell.2022.821649] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/02/2022] [Indexed: 01/25/2023] Open
Abstract
VSIR is a critical immunomodulatory receptor that inhibits T cell effector function and maintains peripheral tolerance. However, the mechanism by which VSIR participates in tumor immunity in the pan-cancer tumor microenvironment remains unclear. This study systematically explored the prognostic and immune profile of VSIR in the tumor microenvironment of 33 cancers. We compared the expression patterns and molecular features of VSIR in the normal and cancer samples both from the public databases and tumor chips. VSIR level was significantly related to patients’ prognosis and could be a promising predictor in many tumor types, such as GBM, KIRC, SKCM, READ, and PRAD. Elevated VSIR was closely correlated with infiltrated inflammatory cells, neoantigens expression, MSI, TMB, and classical immune checkpoints in the tumor microenvironment. Enrichment signaling pathways analysis indicated VSIR was involved in several immune-related pathways such as activation, proliferation, and migration of fibroblast, T cell, mast cell, macrophages, and foam cell. In addition, VSIR was found to widely express on cancer cells, fibroblasts, macrophages, and T cells in many tumor types based on the single-cell sequencing analysis and co-express with M2 macrophage markers CD68, CD163 based on the immunofluorescence staining. Finally, we predicted the sensitive drugs targeting VSIR and the immunotherapeutic value of VSIR. In sum, VSIR levels strongly correlated with the clinical outcome and tumor immunity in multiple cancer types. Therefore, therapeutic strategies targeting VSIR in the tumor microenvironment may be valuable tools for cancer immunotherapy.
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Affiliation(s)
- Yuanyuan Liu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Jingwei Zhang
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zeyu Wang
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xun Zhang
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyu Dai
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wantao Wu
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Nan Zhang
- One-third Lab, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhipeng Wen
- Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, China
| | - Jing Yu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Hao Zhang
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Quan Cheng, ; Tubao Yang, ; Hao Zhang,
| | - Tubao Yang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- *Correspondence: Quan Cheng, ; Tubao Yang, ; Hao Zhang,
| | - Quan Cheng
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Quan Cheng, ; Tubao Yang, ; Hao Zhang,
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12
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Chakraborty A, Roy S, Chakraborty MP, Roy SS, Purkait K, Koley TS, Das R, Acharya M, Mukherjee A. Cytotoxic Ruthenium(II) Complexes of Pyrazolylbenzimidazole Ligands That Inhibit VEGFR2 Phosphorylation. Inorg Chem 2021; 60:18379-18394. [PMID: 34780170 DOI: 10.1021/acs.inorgchem.1c02979] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl- and I-] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P21/n and P21/c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC50 ca. 9-12 μM for 4-8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1-8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7 in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis.
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13
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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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14
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Molecularly targeted therapy for advanced gastrointestinal noncolorectal cancer treatment: how to choose? Past, present, future. Anticancer Drugs 2021; 32:593-601. [PMID: 33929995 DOI: 10.1097/cad.0000000000001071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal cancer is a leading cause of death worldwide. Conventional cytotoxic chemotherapy has been the backbone of advanced gastrointestinal cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. New clinical trials are designed, including classic chemotherapy in association with either small-molecule inhibitors or mAb. During the past few years, remarkable progress in molecular biology of gastrointestinal noncolorectal cancers, the discovery of specific targets and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress. New biological agents with molecularly targeted therapies are now available or currently included in clinical trials (EGFR inhibitors (i), antiangiogenic agents, c-METi, IDHi, FGFR2i, BRAFi, Pi3Ki/AKTi/mTORi, NTRKi). When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. The aim of this review is to focus on the studies that have been completed to date with target therapies and to understand which of these are currently the accepted choice in clinical practice and which need further confirmation and approval for inclusion in guidelines. All these findings will enable to guide clinical practice for oncologists in the design of the next round of clinical trials.
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15
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Xiang R, Rong Y, Ge Y, Song W, Ren J, Fu T. Cell differentiation trajectory predicts patient potential immunotherapy response and prognosis in gastric cancer. Aging (Albany NY) 2021; 13:5928-5945. [PMID: 33612483 PMCID: PMC7950306 DOI: 10.18632/aging.202515] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/29/2020] [Indexed: 04/12/2023]
Abstract
The purpose of this study was to investigate the differentiation trajectory of gastric cancer (GC) cells and its clinical relevance and generate a prognostic risk scoring (RS) signature based on GC differentiation-related genes (GDRGs) to predict overall survival (OS). Integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from GC samples were used for analysis. The cell differentiation trajectory analysis identified three subsets with distinct differentiation states, of which subsets I/II were involved in metabolic disorders, subset II were also associated with hypoxia tolerance, and subset III were related to immune-related pathways. GC samples were divided into three GDRG-based molecular subtypes, and it was found that molecular typing based on cell differentiation successfully predicted patient OS, clinicopathological features, immune infiltration status, and immune checkpoint gene expression. An eight-GDRG-based prognostic RS signature was generated, and the OS of the high-risk group was significantly worse than that of the low-risk group. By integrating the GDRG-based RS signature with prognostic clinicopathological characteristics, a clinicopathologic-genomic nomogram was constructed, and this nomogram yielded strong predictive performance and high accuracy. The study highlights the implication of GC cell differentiation for predicting patient clinical outcome and potential immunotherapy response and proposes a promising treatment direction for GC.
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Affiliation(s)
- Renshen Xiang
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- The Central Laboratory of the First Clinical College of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Yuping Rong
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Yuhang Ge
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wei Song
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- The Central Laboratory of the First Clinical College of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jun Ren
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
- The Central Laboratory of the First Clinical College of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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16
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Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev 2020; 39:1179-1203. [PMID: 32894370 PMCID: PMC7680370 DOI: 10.1007/s10555-020-09925-3] [Citation(s) in RCA: 416] [Impact Index Per Article: 83.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
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Affiliation(s)
- Rachel E Sexton
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Maria Diab
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA.
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17
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Babu N, Pinto SM, Biswas M, Subbannayya T, Rajappa M, Mohan SV, Advani J, Rajagopalan P, Sathe G, Syed N, Radhakrishna VD, Muthusamy O, Navani S, Kumar RV, Gopisetty G, Rajkumar T, Radhakrishnan P, Thiyagarajan S, Pandey A, Gowda H, Majumder P, Chatterjee A. Phosphoproteomic analysis identifies CLK1 as a novel therapeutic target in gastric cancer. Gastric Cancer 2020; 23:796-810. [PMID: 32333232 DOI: 10.1007/s10120-020-01062-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 03/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Phosphorylation is an important regulatory mechanism of protein activity in cells. Studies in various cancers have reported perturbations in kinases resulting in aberrant phosphorylation of oncoproteins and tumor suppressor proteins. METHODS In this study, we carried out quantitative phosphoproteomic analysis of gastric cancer tissues and corresponding xenograft samples. Using these data, we employed bioinformatics analysis to identify aberrant signaling pathways. We further performed molecular inhibition and silencing of the upstream regulatory kinase in gastric cancer cell lines and validated its effect on cellular phenotype. Through an ex vivo technology utilizing patient tumor and blood sample, we sought to understand the therapeutic potential of the kinase by recreating the tumor microenvironment. RESULTS Using mass spectrometry-based high-throughput analysis, we identified 1,344 phosphosites and 848 phosphoproteins, including differential phosphorylation of 177 proteins (fold change cut-off ≥ 1.5). Our data showed that a subset of differentially phosphorylated proteins belonged to splicing machinery. Pathway analysis highlighted Cdc2-like kinase (CLK1) as upstream kinase. Inhibition of CLK1 using TG003 and CLK1 siRNA resulted in a decreased cell viability, proliferation, invasion and migration as well as modulation in the phosphorylation of SRSF2. Ex vivo experiments which utilizes patient's own tumor and blood to recreate the tumor microenvironment validated the use of CLK1 as a potential target for gastric cancer treatment. CONCLUSIONS Our data indicates that CLK1 plays a crucial role in the regulation of splicing process in gastric cancer and that CLK1 can act as a novel therapeutic target in gastric cancer.
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Affiliation(s)
- Niraj Babu
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India.,Manipal Academy of Higher Education, Manipal, 576104, India
| | - Sneha M Pinto
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India.,Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed To Be University), Mangalore, 575018, India
| | | | - Tejaswini Subbannayya
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India.,Mitra Biotech, Bangalore, 560100, India
| | | | - Sonali V Mohan
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India.,Manipal Academy of Higher Education, Manipal, 576104, India
| | - Jayshree Advani
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India
| | - Pavithra Rajagopalan
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India
| | - Nazia Syed
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India
| | | | | | | | - Rekha V Kumar
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, 560029, India
| | - Gopal Gopisetty
- Department of Molecular Oncology, Cancer Institute (WIA), Chennai, 600020, India
| | - Thangarajan Rajkumar
- Department of Molecular Oncology, Cancer Institute (WIA), Chennai, 600020, India
| | | | | | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India.,Manipal Academy of Higher Education, Manipal, 576104, India.,Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.,Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.,Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India.,Manipal Academy of Higher Education, Manipal, 576104, India.,Cancer Precision Medicine, QIMR Berghofer, Royal Brisbane Hospital, Brisbane, QLD, 4029, Australia
| | | | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore, Bangalore, 560066, India. .,Manipal Academy of Higher Education, Manipal, 576104, India. .,Mitra Biotech, Bangalore, 560100, India.
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18
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Hsu A, Chudasama R, Almhanna K, Raufi A. Targeted therapies for gastroesophageal cancers. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1104. [PMID: 33145323 PMCID: PMC7576008 DOI: 10.21037/atm-20-3265] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/30/2020] [Indexed: 12/18/2022]
Abstract
Gastroesophageal cancers are some of the most common malignancies worldwide. A significant portion of patients are diagnosed with advanced or metastatic disease given the insidious nature of gastroesophageal cancers. In the instance where surgical resection for cure is no longer an option, the prognosis is poor and generally less than a year. Traditionally, standard front-line chemotherapy included two- to three-drug regimens with modest improvements in overall survival. Over the past two decades, with increased understanding of the biology of cancer, targeted therapies have been developed to stop the actions of molecules that are key in the growth and spread of cancer cells and have been successful in a number of cancers. In gastroesophageal cancer, these gains have been more modest with limited approval-trastuzumab being incorporated into front-line use in HER2-positive disease, and ramucirumab alone or in combination with paclitaxel becoming the preferred second-line regimen in progressive disease. However, with increased understanding of the biology of cancer, new and promising targeted therapies have emerged along with novel strategies in combining targeted therapies with traditional chemotherapy and immunotherapy. In this article, we will review the use of targeted therapies in the treatment of gastroesophageal cancer and touch upon future treatment strategies and therapeutics currently under investigation.
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Affiliation(s)
- Andrew Hsu
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Rani Chudasama
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Khaldoun Almhanna
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Alexander Raufi
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
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19
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Pauli FP, Martins JR, Paschoalin T, Ionta M, Barbosa MLC, Barreiro EJ. Novel VEGFR‐2 inhibitors with an
N
‐acylhydrazone scaffold. Arch Pharm (Weinheim) 2020; 353:e2000130. [DOI: 10.1002/ardp.202000130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Fernanda P. Pauli
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences Federal University of Rio de Janeiro, CCS Rio de Janeiro RJ Brazil
- Graduate Program in Chemistry (PGQu) Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Juliana R. Martins
- Department of Drugs and Medicines, Institute of Biomedical Sciences Federal University of Alfenas Alfenas Brazil
| | - Thaysa Paschoalin
- Department of Biophysics Federal University of São Paulo São Paulo Brazil
| | - Marisa Ionta
- Department of Drugs and Medicines, Institute of Biomedical Sciences Federal University of Alfenas Alfenas Brazil
| | - Maria Leticia C. Barbosa
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences Federal University of Rio de Janeiro, CCS Rio de Janeiro RJ Brazil
- Faculty of Pharmacy Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Eliezer J. Barreiro
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences Federal University of Rio de Janeiro, CCS Rio de Janeiro RJ Brazil
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20
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Nie S, Yang G, Lu H. Current Molecular Targeted Agents for Advanced Gastric Cancer. Onco Targets Ther 2020; 13:4075-4088. [PMID: 32494161 PMCID: PMC7229784 DOI: 10.2147/ott.s246412] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/20/2020] [Indexed: 12/26/2022] Open
Abstract
Gastric cancer is the third leading cause of malignant tumor-related mortality worldwide. Traditional cytotoxic agents prolong the overall survival and progression-free survival of patients with advanced gastric cancer (AGC) compared to that with best supportive care. Due to the occurrence of serious adverse drug reactions that result in discontinued treatment, the survival benefit in AGC remains unsatisfactory. Systemic chemotherapy regimens have changed greatly, especially since the introduction of trastuzumab. Nevertheless, HER2 positivity is present in only approximately 20% of tumors. Due to the genetic heterogeneity and complexity of patients, there are many studies in progress that are exploring novel targeted drugs as an alternative to chemotherapy or adjuvant treatment in early-stage, progressive, and advanced gastric cancer. On the basis of the differences in gene expression profiles among patients, searching for specific and sensitive predictive biomarkers is important for identifying patients who will benefit from a specific targeted drug. With the development of targeted therapies and available chemotherapeutic drugs, there is no doubt that, over time, more patients will achieve better survival outcomes. Recently, immune checkpoint blockade has been well developed as a promising anticancer strategy. This review outlines the currently available information on clinically tested molecular targeted drugs and immune checkpoint inhibitors for AGC to provide support for decision-making in clinical practice.
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Affiliation(s)
- Shanshan Nie
- Center for Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Guoping Yang
- Center for Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Hongwei Lu
- Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
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21
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Catenacci DVT, Rasco D, Lee J, Rha SY, Lee KW, Bang YJ, Bendell J, Enzinger P, Marina N, Xiang H, Deng W, Powers J, Wainberg ZA. Phase I Escalation and Expansion Study of Bemarituzumab (FPA144) in Patients With Advanced Solid Tumors and FGFR2b-Selected Gastroesophageal Adenocarcinoma. J Clin Oncol 2020; 38:2418-2426. [PMID: 32167861 PMCID: PMC7367551 DOI: 10.1200/jco.19.01834] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE To evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA). PATIENTS AND METHODS FPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer. RESULTS Seventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response. CONCLUSION Overall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.
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Affiliation(s)
| | - Drew Rasco
- The START Center for Cancer Care, San Antonio, TX
| | - Jeeyun Lee
- Samsung Medical Center, Seoul, South Korea
| | - Sun Young Rha
- Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Keun-Wook Lee
- Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Yung Jue Bang
- Seoul National University College of Medicine, Seoul, South Korea
| | - Johanna Bendell
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
| | | | | | - Hong Xiang
- Five Prime Therapeutics, South San Francisco, CA
| | - Wei Deng
- Five Prime Therapeutics, South San Francisco, CA
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22
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Wang X, Yu J, Yang M, Liu L, Gao J, Ren Y, Zhang R, Zhong D, Du N, Fu Z, Jia J, Li Q, Diao J, Zhang J, Guo J, Li X, Song X, Zhang Y, Yu Z, Ma L, Fan Z, Liu Z, Li G, Liang F, Wang H, Gao Y, Yang P, Bai C, Zang A, Ren X. Safety and effectiveness of apatinib in patients with previously treated metastatic gastric cancer: a sub-analysis from the real-world study of apatinib for gastric cancer treatment (AHEAD-G202). Am J Cancer Res 2020; 10:987-996. [PMID: 32266105 PMCID: PMC7136926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 02/20/2020] [Indexed: 06/11/2023] Open
Abstract
Apatinib, a VEGFR2 receptor tyrosine kinase inhibitor, showed survival benefits in Asian patients with heavily pretreated advanced gastric cancer. However, the adverse event (AEs) profile of apatinib has limited its use. Dosing schedules are used to alleviate toxicities despite no supportive evidence. This study aimed to analyze the toxicity and effectiveness of apatinib alone, especially with different dosing strategies in advanced gastric cancer patients under a real-world setting. Data from the subpopulation of patients who failed ≥2 chemotherapy regimens enrolled in the AHEAD-G202 trial were analyzed. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Totally 120 patients were included into three groups by the initial daily doses: 43 (35.8%) patients in the low-dose (250 mg) group, 67 (55.8%) patients in the mid-dose (425 mg to 500 mg) group, and 10 (8.3%) patients in the high-dose (675 to 850 mg) group. Grade 3/4 treatment-emergent AEs were infrequent (<5%), with the most commonly reported grade 3/4 AEs being hand-foot syndrome (4.2%), hypertension (4.2%,), fatigue (4.2%), and difficulty in swallowing (4.2%) which gradually decreased among the high-, mid-, and low-dose groups. The median OS and PFS were 6.33 months (95% CI, 4.57-7.73) and 3.83 months (95% CI: 1.40-4.20), respectively and were comparable among the three doses groups. We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice.
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Affiliation(s)
- Xiang Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesBeijing 100032, China
| | - Junyan Yu
- Department of Oncology, Peace Hospital of Changzhi Medical CollegeChangzhi 046000, China
| | - Mudan Yang
- Digestive Department of Oncology, Shanxi Tumor HospitalTaiyuan 030013, China
| | - Likun Liu
- Oncology Department, Shanxi Provincial Hospital of Traditional Chinese MedicineTaiyuan 030012, China
| | - Jinghua Gao
- Department of Medical Oncology, Cangzhou Central HospitalCangzhou 061000, China
| | - Yuchuan Ren
- Oncology Department, Yangquan First People’s HospitalYangquan 045000, China
| | - Ruixing Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050071, China
| | - Diansheng Zhong
- Department of Medical Oncology, Tianjin Medical University General HospitalTianjin 300052, China
| | - Nan Du
- Department of Medical Oncology, Fourth Medical Center of PLA General HospitalBeijing 100048, China
| | - Zhanzhao Fu
- Department of Medical Oncology, First Hospital of QinhuangdaoQinhuangdao 066001, China
| | - Junmei Jia
- Department of Medical Oncology, First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Qingshan Li
- Department of Medical Oncology, Affiliated Hospital of Chengde Medical UniversityChengde 067000, China
| | - Jianfeng Diao
- Department of Medical Oncology, Datong Second People’s HospitalDatong 037005, China
| | - Junping Zhang
- Department of Medical Oncology, Shanxi Academy of Medical Sciences, Shanxi Dayi HospitalTaiyuan 030032, China
| | - Jun Guo
- Department of Medical Oncology, Xingtai People’s Hospital, Hebei Medical University Affiliated HospitalXingtai 054031, China
| | - Xiaomei Li
- Department of Medical Oncology, Chinese PLA General Hospital, Medical School of Chinese PLABeijing 100039, China
| | - Xiang Song
- Department of Medical Oncology, Second Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Yan Zhang
- Department of Medical Oncology, Shijiazhuang People’s HospitalShijiazhuang 050011, China
| | - Zhonghe Yu
- Department of Medical Oncology, Seventh Medical Center of PLA General HospitalBeijing 100700, China
| | - Liwen Ma
- Department of Tumor Chemotherapy and Radiology, Peking University Third HospitalBeijing 100191, China
| | - Zaiwen Fan
- Department of Medical Oncology, Air Force General Hospital, PLABeijing 100142, China
| | - Zheng Liu
- Department of Radiology, Handan Central HospitalHandan 056001, China
| | - Guozhong Li
- Department of Medical Oncology, Peking University Binhai HospitalTianjin 300450, China
| | - Feng Liang
- Department of General Surgery, Fifth Medical Center of PLA General HospitalBeijing 100071, China
| | - Huaqing Wang
- Department of Medical Oncology, Tianjin People’s HospitalTianjin 30000, China
| | - Yunge Gao
- Department of Hematology and Oncology, Strategic Support Force Characteristic Medical Center/Former The 306 Hospital of PLABeijing 100101, China
| | - Ping Yang
- Department of Medical Oncology, Sixth Medical Center of PLA General HospitalBeijing 100048, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesBeijing 100032, China
| | - Aimin Zang
- Department of Medical Oncology, Affiliated Hospital of Hebei UniversityBaoding 071000, China
| | - Xiubao Ren
- Department of Biotherapy, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China
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Narasimhamurthy KH, Chandra, Swaroop TR, Jagadish S, Rangappa KS. Synthesis of Piperidine Conjugated Dihydroquinazolin-4(1H)-ones and their Antiproliferative Activity, Molecular Docking Studies and DFT Calculations. LETT DRUG DES DISCOV 2019. [DOI: 10.2174/1570180816666190613120349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Xanthatin, fluoropyrimidine and thienopyrimidine, pyrazolopyrimidine,
pyrimidine carboxamides, and SKLB1002 are reported as VEGFR2 tyrosine kinase inhibitors.
Recently, many studies related to different heterocycles conjugated with dihydroquinazolinones are
known to have very good biological activities. In this study, we are intended to explore the cytotoxic
studies of piperidine conjugated dihydroquinazolinones against colorectal/colon cancer cell lines and
along with molecular docking studies and DFT calculations.
Methods:
The colorectal/colon cell lines HCT116 and A549 cell lines were treated with these
compounds and cytotoxic activities were evaluated by MTT dye uptake method. We performed
molecular modelling for compound 3d using the Auto Dock software. The binding of compound 3d
with target proteins was studied with the collection of experimentally determined PDB database.
Optimized geometry by DFT calculations was performed with B3LYP/6-31G (d) basis set.
Results:
Piperidine-conjugated dihydroquinazolinone analogues displayed anticancer activity.
Particularly, the compound 3d with electron-withdrawing substituents on a phenyl ring showed
significant cytotoxicity against HCT116 and A549 cell lines. Molecular docking studies proved that
the compound 3d has good fitting by forming hydrogen bonds with amino acid residues at the active
sites of VEGFR2. The HOMO, LUMO, their energies and UV visible spectrum were predicted using
DFT calculations.
Conclusion:
Four piperidine-conjugated dihydroquinazolinones were synthesized and evaluated
against colorectal and colon cancer cell lines. Compound 3d significantly inhibited the growth of
HCT116 and A549. Molecular docking studies displayed good fitting of compound 3d by forming
different H-bonds with the amino acid at the active sites of the VEGFR2 target. Using a theoretical
approach, we optimized HOMO and LUMO plots for the compound 3d.
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Affiliation(s)
| | - Chandra
- Department of Physics, National Institute of Engineering, Mysuru 570008, India
| | | | - Swamy Jagadish
- Department of Studies in Biochemistry, Manasagangotri, University of Mysore, Mysuru 570006, India
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24
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Nanoformulations of small molecule protein tyrosine kinases inhibitors potentiate targeted cancer therapy. Int J Pharm 2019; 573:118785. [PMID: 31678384 DOI: 10.1016/j.ijpharm.2019.118785] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/05/2019] [Accepted: 10/10/2019] [Indexed: 01/08/2023]
Abstract
Protein tyrosine kinases (PTKs) are closely related to tumor development and usually participate in apoptosis, DNA repair, and cell proliferation by activating signaling pathways. Therefore, PTKs have become the most promising targets for cancer therapy. In recent years, a large number of studies on the mechanism of tyrosine kinase activation have indicated that tyrosine kinase inhibitors (TKIs) have important clinical significance and application prospects as targeted anticancer drugs because they can effectively block certain cellular signaling pathways, inhibit tumor metastases and reduce tumor proliferation. Although the increasing emergence of anticancer drug resistance limits the clinical application of TKIs, emerging nanotechnology has made it possible to solve this problem. In this work, the state-of-art of small molecule protein tyrosine kinase inhibitors and the applications of drug delivery systems for TKIs are reviewed, and the potentials and challenges for future research of small molecule TKIs are addressed.
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25
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Selim JH, Shaheen S, Sheu WC, Hsueh CT. Targeted and novel therapy in advanced gastric cancer. Exp Hematol Oncol 2019; 8:25. [PMID: 31632839 PMCID: PMC6788003 DOI: 10.1186/s40164-019-0149-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 09/28/2019] [Indexed: 12/14/2022] Open
Abstract
The systemic treatment options for advanced gastric cancer (GC) have evolved rapidly in recent years. We have reviewed the recent data of clinical trial incorporating targeted agents, including inhibitors of angiogenesis, human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition, epidermal growth factor receptor, mammalian target of rapamycin, claudin-18.2, programmed death-1 and DNA. Addition of trastuzumab to platinum-based chemotherapy has become standard of care as front-line therapy in advanced GC overexpressing HER2. In the second-line setting, ramucirumab with paclitaxel significantly improves overall survival compared to paclitaxel alone. For patients with refractory disease, apatinib, nivolumab, ramucirumab and TAS-102 have demonstrated single-agent activity with improved overall survival compared to placebo alone. Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability-high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non-inferior outcome in first-line treatment compared to chemotherapy. This review summarizes the current state and progress of research on targeted therapy for advanced GC.
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Affiliation(s)
- Julie H. Selim
- School of Pharmacy, Loma Linda University, Loma Linda, CA 92350 USA
| | - Shagufta Shaheen
- Division of Oncology, Stanford Cancer Center, Stanford, CA 94304 USA
| | - Wei-Chun Sheu
- Department of Internal Medicine, Richmond University Medical Center, Staten Island, NY 10310 USA
| | - Chung-Tsen Hsueh
- Division of Medical Oncology and Hematology, Department of Medicine, Loma Linda University, 11175 Campus Street, CSP 11015, Loma Linda, CA 92354 USA
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26
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Butters O, Young K, Cunningham D, Chau I, Starling N. Targeting Vascular Endothelial Growth Factor in Oesophagogastric Cancer: A Review of Progress to Date and Immunotherapy Combination Strategies. Front Oncol 2019; 9:618. [PMID: 31380271 PMCID: PMC6647870 DOI: 10.3389/fonc.2019.00618] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 06/24/2019] [Indexed: 12/11/2022] Open
Abstract
In 2014, the survival benefits seen in REGARD and RAINBOW studies led the way for the regulatory approval of ramucirumab in the second line setting in oesophagogastric (OG) cancer. Trials of other drugs targeting the vascular endothelial growth factor (VEGF) pathway have met with mixed results but this remains an important pathway for evaluation in OG cancer. Perhaps the most interesting ongoing trials are those which target VEGF in combination with immunotherapy, which have a sound scientific rationale. Given the emerging role of immunotherapy in OG cancer, this is an important area of innovation. This review aims to outline targeting VEGF in OG cancer, the rationale behind the continued interest in this mechanism and possible future directions in combination with immunotherapy.
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Affiliation(s)
| | | | | | | | - Naureen Starling
- Gastrointestinal Unit, Royal Marsden Hospital, London, United Kingdom
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27
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Hironaka S. Anti-angiogenic therapies for gastric cancer. Asia Pac J Clin Oncol 2019; 15:208-217. [PMID: 31111678 DOI: 10.1111/ajco.13174] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 05/07/2019] [Indexed: 12/12/2022]
Abstract
Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti-angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR)-2 monoclonal antibodies, VEGF-Trap and VEGFR tyrosine kinase inhibitors, the anti-VEGFR-2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second-line chemotherapy. Additionally, apatinib, a selective VEGFR-2 tyrosine kinase inhibitor, prolonged survival as a third-line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti-angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.
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Affiliation(s)
- Shuichi Hironaka
- Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan
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Amerizadeh F, Khazaei M, Maftouh M, Mardani R, Bahrami A. miRNA Targeting Angiogenesis as a Potential Therapeutic Approach in the Treatment of Colorectal Cancers. Curr Pharm Des 2019; 24:4668-4674. [DOI: 10.2174/1381612825666190110161843] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/27/2018] [Accepted: 01/01/2019] [Indexed: 12/11/2022]
Abstract
Angiogenesis refers to the formation of recent blood vessels, which is one of the characteristics of
cancer progression and it has been deliberated as a putative target to the treatment of many kinds of cancers. The
VEGF signaling substrate is very important for angiogenesis and is commonly high-regulated in tumors. As a
result, this molecule has attracted the attention of most of the researchers to develop antiangiogenic therapies. We
have presented that VEGF blockage in neoadjuvant setting via bevacizumab, aflibercept and sunitinib not only
has revealed some promising benefits but also has shown a large negative outcome in the adjuvant trials. However,
at an advanced stage of tumors, suppression of VEGF alone is inadequate to stop advancement, encouraging
drug resistance, and probably enhancing metastasis and invasion in the tumor microenvironment, thereby suggesting
the therapeutic potential of targeting angiogenic pathways in gastrointestinal cancers.
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Affiliation(s)
- Forouzan Amerizadeh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Maftouh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Mardani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
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29
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Wen S, Shao G, Zheng J, Zeng H, Luo J, Gu D. Apatinib regulates the cell proliferation and apoptosis of liver cancer by regulation of VEGFR2/STAT3 signaling. Pathol Res Pract 2019; 215:816-821. [PMID: 30686547 DOI: 10.1016/j.prp.2019.01.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/02/2019] [Accepted: 01/17/2019] [Indexed: 12/31/2022]
Abstract
Liver cancer is the third most common cause of cancer related death worldwide. Apatinib showed satisfactory efficacy in various types of cancers, including breast cancer, malignant fibrous histiocytoma and liver cancer. However, how did Apatinib function in liver cancer is largely unknown. mRNA levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) as well as protein levels of VEGF and p-VEGFR2 were obviously higher in liver cancer cell line SMCC7721 than in normal liver cell LO2. Apatinib significantly inhibited the mRNA levels of VEGF and VEGFR2 as well as protein levels of VEGF and p-VEGFR2 compared with those in control group. At 12, 24 and 48 h after corresponding treatments, compared with the control group, Apatinib significantly lowered the cell viability of SMCC7721 cells, while transfection of si-signal transducer and activator of transcription 3 (siSTAT3) further augmented the effects of Apatinib. At 48 h after treatment, compared with the control group, Apatinib significantly upregulated the cell apoptosis rate of SMCC7721 cells, which was further induced by the transfection of siSTAT3. Compared with control group, Apatinib significantly induced BAX/Bcl-2 ratio elevation, reduced p-STAT3 and p-VEGFR2 expression, which were significantly augmented by the treatment of siSTAT3. In conclusion, Apatinib inhibited the cell proliferation and promoted the cell apoptosis of liver cancer by inhibiting the activation of VEGFR2/STAT3.
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Affiliation(s)
- Song Wen
- Department of Interventional Treatment, Zhejiang Cancer Hospital, Hangzhou 310006, China
| | - Guoliang Shao
- Department of Interventional Treatment, Zhejiang Cancer Hospital, Hangzhou 310006, China.
| | - Jiaping Zheng
- Department of Interventional Treatment, Zhejiang Cancer Hospital, Hangzhou 310006, China
| | - Hui Zeng
- Department of Interventional Treatment, Zhejiang Cancer Hospital, Hangzhou 310006, China
| | - Jun Luo
- Department of Interventional Treatment, Zhejiang Cancer Hospital, Hangzhou 310006, China
| | - Danlin Gu
- Department of Integrated Traditional & Western Medicine, Zhejiang Cancer Hospital, Hangzhou, 310006, China
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30
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Hacker U, Lordick F. Anti-angiogenics in Gastroesophageal Cancer. TUMOR ANGIOGENESIS 2019:395-414. [DOI: 10.1007/978-3-319-33673-2_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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31
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Dahdaleh FS, Turaga KK. Evolving Treatment Strategies and Outcomes in Advanced Gastric Cancer with Peritoneal Metastasis. Surg Oncol Clin N Am 2018; 27:519-537. [PMID: 29935687 DOI: 10.1016/j.soc.2018.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) has a predilection to metastasize to the peritoneum, denoting a poor prognosis. Treatment strategies available for advanced GC have significantly evolved over time and can be categorized into systemic, regional, and surgical. Although systemic therapies have been the mainstay for the treatment of advanced GC, their ability in achieving long-term survival in patients with peritoneal involvement is modest at best. This article describes advances in combined modality treatment of peritoneal metastases, specifically with an emphasis on peritoneal-directed therapies.
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Affiliation(s)
- Fadi S Dahdaleh
- Complex General Surgical Oncology, Section of General Surgery/Surgical Oncology, The University of Chicago Medicine, 5841 South Maryland Avenue, Room S214, MC 5094, Chicago, IL 60637, USA
| | - Kiran K Turaga
- The University of Chicago Medicine, Section of General Surgery/Surgical Oncology, 5841 South Maryland Avenue, Room G207, MC 5094, Chicago, IL 60637, USA.
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32
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Li R, Li J, Wang X, Liang P, Gao J. Detection of gastric cancer and its histological type based on iodine concentration in spectral CT. Cancer Imaging 2018; 18:42. [PMID: 30413174 PMCID: PMC6230291 DOI: 10.1186/s40644-018-0176-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 10/29/2018] [Indexed: 12/19/2022] Open
Abstract
Background Computed tomography (CT) imaging is the most common imaging modality for the diagnosis and staging of gastric cancer. The aim of this study is was to prospectively explore the ability of quantitative spectral CT parameters in the detection of gastric cancer and its histologic types. Methods A total of 87 gastric adenocarcinoma (43 poorly and 44 well-differentiated) patients and 36 patients with benign gastric wall lesions (25 inflammation and 11 normal), who underwent dual-phase enhanced spectral CT examination, were retrospectively enrolled in this study. Iodine concentration (IC) and normalized iodine concentration (nIC) during arterial phase (AP) and portal venous phase (PP) were measured thrice in each patient by two blinded radiologists. Moreover, intraclass correlation coefficient (ICC) was used to assess the interobserver reproducibility. Differences of IC and nIC values between gastric cancer and benign lesion groups were compared using Mann-Whitney U test. Furthermore, the gender, age, location, thickness and histological types of gastric adenocarcinoma were analyzed by Mann-Whitney U test or Kruskal-Wallis H test. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of IC and nIC values, and the optimal cut-off value was calculated with Youden J. Results An excellent interobserver agreement (ICC > 0.6) was achieved for IC. Notably, the values of ICAP, ICPP, nICAP and nICPP were significantly higher in gastric cancer group (Z = 5.870, 3.894, 2.009 and 10.137, respectively; P < 0.05) than those in benign lesion group. Additionally, the values of ICAP, ICPP, nICAP and nICPP were significantly higher in poorly differentiated gastric adenocarcinoma group (Z = 4.118, 5.637, 6.729 and 2.950, respectively; P < 0.005) than those in well-differentiated gastric adenocarcinoma group. There were no statistically significant differences in the values of ICAP, ICPP, nICAP and nICPP between age, gender, tumor thickness and tumor location. Furthermore, the area under the curve (AUC) values of ICAP, nICAP, ICPP and nICPP were 0.745, 0.584, 0.662, and 0.932, respectively, for gastric cancer detection; while 0.756, 0.919, 0.851 and 0.684, respectively, in discriminating poorly differentiated gastric adenocarcinoma. Conclusion IC values exhibited great potential in the preoperative and non-invasive diagnosis of gastric cancer and its histological types. In particular, nICPP is more effective for the identification of gastric cancer, whereas nICAP is more effective in discriminating poorly differentiated gastric adenocarcinoma.
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Affiliation(s)
- Rui Li
- Department of Radiology, the First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Jing Li
- Department of Radiology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127, Dongming Road, Zhengzhou, 450008, Henan, China
| | - Xiaopeng Wang
- Department of Radiology, the First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Pan Liang
- Department of Radiology, the First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Jianbo Gao
- Department of Radiology, the First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China.
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33
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Bai ZG, Zhang ZT. A systematic review and meta-analysis on the effect of angiogenesis blockade for the treatment of gastric cancer. Onco Targets Ther 2018; 11:7077-7087. [PMID: 30410364 PMCID: PMC6200090 DOI: 10.2147/ott.s169484] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Introduction To date, anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb, bevacizumab), anti-VEGF receptor mAb (ramucirumab) and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (sunitinib, sorafenib and apatinib) have been tested in the clinical trials. Materials and methods In the current study, results of 32 clinical trials (24 Phase I or II, 8 Phase III) were systematically reviewed and meta-analysis was performed in 8 Phase III trial results. Results It was found that median overall survival (OS) time and progression-free survival (PFS) time were significantly longer in the patients treated with antiangiogenic reagents compared to that in the patients with placebo when all of 8 Phase III clinical trials were analyzed together (OS: odds ratio = 0.805, 95% CI: 0.719–0.901, P < 0.001; PFS: odds ratio = 0.719, 95% CI: 0.533–969, P = 0.030). Conclusion Meta-analysis on bevacizumab (4 out 8 Phase III trials) indicated that neither OS nor PFS was significantly different between the groups treated with bevacizumab or placebo with or without combination of other chemotherapeutic reagents (OS: odds ratio = 0.909, 95% CI: 0.780–1.059, P = 0.221; PFS: odds ratio = 0.985, 95% CI: 0.865–1.122, P = 0.826). By contrast, meta-analysis on ramucirumab (3 out of 8 Phase III trials) revealed that ramucirumab was significantly favored in the treatment of gastric cancer with significant different OS between the two groups (odds ratio = 0.720, 95% CI: 0.604–0.858, P < 0.001). In addition, patients treated with VEGF or VEGFR blockers had higher morbidity of hypertension and neutropenia, but lower risk of side effects of vomiting and anemia. These findings suggest that addition of antiangiogenesis reagents, especially anti-VEGFR-mAb, to the first- or second-line chemotherapy could prolong patient’s OS and PFS time in the advanced or metastatic gastric cancer.
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Affiliation(s)
- Zhi-Gang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research and National Clinical Research Center for Digestive Diseases, Beijing 100050, People's Republic of China,
| | - Zhong-Tao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research and National Clinical Research Center for Digestive Diseases, Beijing 100050, People's Republic of China,
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Zhao D, Hou H, Zhang X. Progress in the treatment of solid tumors with apatinib: a systematic review. Onco Targets Ther 2018; 11:4137-4147. [PMID: 30050305 PMCID: PMC6056166 DOI: 10.2147/ott.s172305] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
With the investigation of molecular targets, many agents, such as trastuzumab and ramucirumab, have attained a positive outcome in oncotherapy. Vascular endothelial growth factor (VEGF) is considered a potent factor in angiogenesis and plays an important role in the growth of tumors. Moreover, both VEGF and its receptor are usually excessively expressed in solid tumors and could be hopeful targets for the treatment of neoplasms. Apatinib (YN968D1) is an oral small-molecule tyrosine kinase inhibitor of VEGFR-2. By inhibiting several signaling transduction pathways, it restrains angiogenesis and subsequently controls tumorigenesis. According to current studies, apatinib shows promising application in various solid tumors as a post-second- and post-third-line treatment. It could significantly improve the median overall survival and progression-free survival of patients with tolerated adverse reactions. This paper aims to summarize the recent research on apatinib including the mechanism, pharmacokinetics, trials, adverse reactions, and prospect as a treatment.
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Affiliation(s)
- Deze Zhao
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China,
| | - Helei Hou
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China,
| | - Xiaochun Zhang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China,
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Abbas M, Faggian A, Sintali DN, Khan GJ, Naeem S, Shi M, Dingding C. Current and future biomarkers in gastric cancer. Biomed Pharmacother 2018; 103:1688-1700. [DOI: 10.1016/j.biopha.2018.04.178] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023] Open
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Stomatitis and VEGFR-Tyrosine Kinase Inhibitors (VR-TKIs): A Review of Current Literature in 4369 Patients. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5035217. [PMID: 29992147 PMCID: PMC5994328 DOI: 10.1155/2018/5035217] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 02/25/2018] [Accepted: 03/05/2018] [Indexed: 12/27/2022]
Abstract
Background Multitargeted tyrosine kinase inhibitors (TKIs) represent a new class of target-specific antineoplastic agents. These agents show some specific adverse events such as fatigue/asthenia, anorexia/loss of appetite, dysgeusia, diarrhea/abdominal pain, hypothyroidism, hypertension, myelosuppression, and stomatitis. Materials and Methods A systematic search was performed on PubMed online database using a combination of MESH terms and free text words, “sunitinib” OR “sorafenib” OR “axitinib” OR “cabozantinib” OR “pazopanib” OR “regorafenib” OR “nintedanib” OR “vatalanib” combined through the use of Boolean operator AND with the key words “stomatitis” OR “mucositis,” (i) on human subjects, (ii) written in the English language, and (iii) reporting about the incidence of stomatitis or oral mucositis. Results The incidence of stomatitis of any grade was 35.2% for sunitinib, 20.52% for sorafenib, 20.63% for axitinib, and 34.21% for cabozantinib. All the agents showed high rates of low-grade stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was very low. Conclusions Analysis of the reports with patients treated with sunitinib, sorafenib, axitinib, and cabozantinib showed a clear prevalence of stomatitis grade 1 or grade 2. These data differ from those of patients treated with conventional chemotherapy in which mucositis is predominantly of grade 3 or grade 4.
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Tamma R, Annese T, Ruggieri S, Marzullo A, Nico B, Ribatti D. VEGFA and VEGFR2 RNAscope determination in gastric cancer. J Mol Histol 2018; 49:429-435. [PMID: 29761299 DOI: 10.1007/s10735-018-9777-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide. Several studies on angiogenic blocking agents in gastric cancer revealing promising results by the use of monoclonal antibodies against VEGFA or its receptor VEGFR2 or against VEGFA activating pathway. The validation of biomarkers useful to better organize the clinical trials involving anti-angiogenic therapies is crucial. Molecular markers such as RNA are increasingly used for cancer diagnosis, prognosis, and therapy guidance as in the case of the targeted therapies concerning the inhibition of angiogenesis. The aim of this study is to set the conditions for evaluating the expression of VEGFA and VEGFR2 in gastric cancer specimens and in healthy gastric mucosa by the use of RNAscope, a novel RNA in situ hybridization (ISH) method that allows the visualization of a specific gene expression in individual cells. We found the increased expression of VEGFA in the tubular glands and VEGFR2 in the endothelium of gastric cancer samples mainly in the T2, T3 and T4 stages of tumor progression as compared to the healthy controls. These results obtained by the application of this highly sensitive method for oligonucleotide detection the role of angiogenesis in gastric cancer progression already highlighted by conventional immunohistochemical methods, and offer significant promise as a new platform for developing and implementing RNA-based molecular diagnostics also in the conditions in which immunohistochemistry is not applicable.
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Affiliation(s)
- Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Simona Ruggieri
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Andrea Marzullo
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Beatrice Nico
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy.
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Sun Z, Cheng X, Ge Y, Shao L, Xuan Y, Yan G. An application study of low-dose computed tomography perfusion imaging for evaluation of the efficacy of neoadjuvant chemotherapy for advanced gastric adenocarcinoma. Gastric Cancer 2018; 21:413-420. [PMID: 28871423 DOI: 10.1007/s10120-017-0763-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND This study used low-dose computed tomography (CT) perfusion imaging technology to evaluate the efficacy of neoadjuvant chemotherapy in patients with advanced gastric adenocarcinoma and to determine whether any of the perfusion parameters could predict tumor response to chemotherapy. METHODS Forty patients with gastric adenocarcinoma (T3-4NxM0) received three cycles of neoadjuvant chemotherapy and low-dose spiral CT perfusion imaging prior to and after the first and third series of chemotherapy. We calculated tissue blood flow (BF) and blood volume (BV) using commercial software. One-way analysis of variance (ANOVA) was used to detect any significant variation of the tested parameters between different times of scanning. Spearman's test was used to evaluate the correlation among perfusion parameters, tumor size and pathological efficacy grade, and clinical response after chemotherapy, respectively. A receiver-operating characteristic analysis was used to determine the optimal diagnostic cutoff value for changes in perfusion parameters and tumor size. RESULTS One-way ANOVA showed significant differences in BF and BV values between those before and after chemotherapy (p < 0.01). The BF, BV and size reduction rate after three series of chemotherapy were significantly correlated with pathological efficacy grade. BF and BV values after the first and third series of chemotherapy were also significantly correlated with clinical response (p < 0.01, respectively). The diagnostic sensitivity and specificity of the BV reduction rate were higher than those of size reduction rate. CONCLUSIONS Low-dose CT perfusion imaging is a valuable tool that permits microcirculation evaluation and therefore can evaluate the efficacy of neoadjuvant chemotherapy in patients with advanced gastric adenocarcinoma.
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Affiliation(s)
- Zongqiong Sun
- Department of Radiology, Affiliated Hospital, Jiangnan University, Wuxi, People's Republic of China
| | - Xiaofang Cheng
- Department of Radiology, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Huiai Hospital, Guangzhou, People's Republic of China
| | - Yuxi Ge
- Department of Radiology, Affiliated Hospital, Jiangnan University, Wuxi, People's Republic of China
| | - Lin Shao
- Department of Radiology, Affiliated Hospital, Jiangnan University, Wuxi, People's Republic of China
| | - Yinghua Xuan
- Department of Basic Medicine, Jiangnan University Medical School, Wuxi, People's Republic of China
| | - Gen Yan
- Department of Radiology, Affiliated Hospital, Jiangnan University, Wuxi, People's Republic of China.
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Kim S, Barzi A, Rajdev L. Biomarker-driven targeted therapies for gastric/gastro-esophageal junction malignancies. Semin Oncol 2018; 45:133-150. [PMID: 30262395 DOI: 10.1053/j.seminoncol.2018.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 09/13/2017] [Accepted: 03/07/2018] [Indexed: 02/08/2023]
Abstract
Gastroesophageal malignancies often contain high amounts of genetic and molecular alterations that result in an aggressive disease capable of rapidly metastasizing to distant organs and early development of drug resistance. Most patients in the Western hemisphere present with locally advanced or metastatic disease that is treated with systemic chemotherapy used either in the neoadjuvant or palliative setting, respectively. This article will review the various recent advances in the development of targeted therapies for the treatment of advanced gastric and gastroesophageal cancer.
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Affiliation(s)
- Salem Kim
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY
| | - Afsaneh Barzi
- Keck School of Medicine at University of Southern California
| | - Lakshmi Rajdev
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
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Ma JL, Zhang T, Suo FZ, Chang J, Wan XB, Feng XJ, Zheng YC, Liu HM. Lysine-specific demethylase 1 activation by vitamin B2 attenuates efficacy of apatinib for proliferation and migration of gastric cancer cell MGC-803. J Cell Biochem 2018; 119:4957-4966. [PMID: 29384217 DOI: 10.1002/jcb.26741] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 01/25/2018] [Indexed: 12/29/2022]
Abstract
B vitamins play an essential role in the biosynthesis of nucleotides, replication of DNA, supply of methyl-groups, growth and repair of cells, aberrancies of which have all been implicated in carcinogenesis. Although the potential role of vitamin B in relation to the risk of cancer, including breast, and colorectal cancer, has been investigated in several observational studies, the mechanism of action is still unclear. In this study, vitamin B2 exhibited efficient activation of LSD1 by occupying the active sites where FAD stands. Interestingly, vitamin B2 significantly downregulated expression of CD86, a sensitive surrogate biomarker of LSD1 inhibition, and showed marked activation of gastric cancer cell migration and invasion. Meanwhile, vitamin B2 induced activation of LSD1 may attenuate the proliferation inhibition, and anti-migration effects of apatinib in gastric cancer cells. These findings suggested that vitamin B supplementation may interfere with the efficacy of apatinib in patients with gastric cancer.
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Affiliation(s)
- Jin-Lian Ma
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Ting Zhang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Feng-Zhi Suo
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Jiao Chang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiang-Bin Wan
- Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China
| | - Xue-Jian Feng
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Yi-Chao Zheng
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China.,National Center for International Research of Micro-nano Molding Technology & Key Laboratory for Micro Molding Technology of Henan Province, Zhengzhou University, Zhengzhou, Henan, China
| | - Hong-Min Liu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
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Liu D, Ma X, Xiao D, Jia Y, Wang Y. Efficacy and safety of targeting VEGFR drugs in treatment for advanced or metastatic gastric cancer: a systemic review and meta-analysis. Oncotarget 2018; 9:8120-8132. [PMID: 29487720 PMCID: PMC5814287 DOI: 10.18632/oncotarget.23429] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 11/29/2017] [Indexed: 12/21/2022] Open
Abstract
The value of targeting VEGFR (vascular endothelial growth factor receptor) drugs has demonstrated encouraging anti-cancer activity in advanced solid tumors within current clinical trials. This study aimed to serve as the first systemic review to assess their safety and efficacy according to biochemical characteristics of targeting VEGFR drugs in gastric cancer. We analyzed eight clinical trials on targeting VEGFR drugs in gastric cancer. Results showed that targeting VEGFR drugs significantly improved overall survival (OS) [Hazard Ratio (HR) 0.69, 95% confidence interval (CI) (0.55, 0.83), P < 0.001], progression free survival (PFS) [HR 0.50, 95% CI (0.34, 0.66), P < 0.001], disease control rate (DCR) [Odds Ratio (OR) 3.83, 95% CI (2.39, 6.15), P < 0.001] and significantly decreased the progressive disease rate(PDR)[OR 0.45, 95% CI (0.34, 0.59), P < 0.001], but not objective response rate (ORR) [OR 1.46, 95% CI (0.93, 2.29), P = 0.098]. Further subgroup revealed that VEGFR antibody (VEGFR-Ab) drugs were superior to VEGFR tyrosine kinase inhibitor (VEGFR-TKI) drugs in terms of the OS, PFS and PDR. To determine the toxic effect of targeting VEGFR drugs, the relative risk of adverse events (grade ≥ 3) of special interest(AESIs) were estimated. Most of these were predictable and manageable. Furthermore, less AESIs were observed in the VEGFR-Ab than the VEGFR-TKI drugs. In conclusion, VEGFR drugs were effective targeted therapy in advanced or metastatic gastric cancer, and its toxicity is within a controllable range. VEGFR-Ab drugs were more effective than VEGFR-TKI drugs in terms of the OS, PFS and PDR of gastric cancer patients with little toxicity.
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Affiliation(s)
- Duanrui Liu
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
| | - Xiaoli Ma
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
| | - Dongjie Xiao
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
| | - Yanfei Jia
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
- Shandong Province Key Lab of Tumor Target Molecule, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
| | - Yunshan Wang
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
- Shandong Province Key Lab of Tumor Target Molecule, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, People's Republic of China
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Mawalla B, Yuan X, Luo X, Chalya PL. Treatment outcome of anti-angiogenesis through VEGF-pathway in the management of gastric cancer: a systematic review of phase II and III clinical trials. BMC Res Notes 2018; 11:21. [PMID: 29329598 PMCID: PMC5767044 DOI: 10.1186/s13104-018-3137-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/06/2018] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Advanced gastric cancer poses a therapeutic challenge worldwide. In randomised clinical trials, anti-VEGF has been reported as an essential agent for the treatment of advanced gastric cancer. This review aims at assessing the treatment outcome of anti-angiogenesis therapy through the VEGF pathway in the management of patients with advanced gastric cancer. RESULTS During this review, 38 clinical trials were identified. Of these, 30 clinical trials were excluded, leaving eight trials of phase II and III. Ramucirumab, as a second line treatment of advanced gastric cancer, decreases the risk of disease progression (37-52%) and death (19-22%). Compare ramucirumab and bevacizumab in combination with traditional chemotherapy; ramucirumab has shown to improve progression-free survival and overall survival. Apatinib tyrosine kinase inhibitor combined with traditional chemotherapy has shown to improve overall response rate and progression-free survival with marginal improvements in overall survival. Chemotherapy, in combination with anti-VEGF drugs, in the management of advanced gastric cancer significantly improves the outcome of overall response rate, progression-free survival and overall survival when compared to chemotherapy alone. Therefore, we recommend that anti-VEGF drugs are the drugs of choice in the management of patients with advanced gastric cancer.
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Affiliation(s)
- Brian Mawalla
- Department of Oncology, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, Hubei, China.
| | - Xianglin Yuan
- Department of Oncology, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, Hubei, China
| | - Xiaoxiao Luo
- Department of Oncology, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, Hubei, China
| | - Phillip L Chalya
- Department of Oncology, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, Hubei, China.,Department of Surgery, Bugando Medical Centre, Mwanza, Tanzania
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Chen LT, Oh DY, Ryu MH, Yeh KH, Yeo W, Carlesi R, Cheng R, Kim J, Orlando M, Kang YK. Anti-angiogenic Therapy in Patients with Advanced Gastric and Gastroesophageal Junction Cancer: A Systematic Review. Cancer Res Treat 2017; 49:851-868. [PMID: 28052652 PMCID: PMC5654167 DOI: 10.4143/crt.2016.176] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 12/20/2016] [Indexed: 02/08/2023] Open
Abstract
Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.
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Affiliation(s)
- Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes and National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Do-Youn Oh
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Winnie Yeo
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | | | | | | | | | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Dai J, Belum VR, Wu S, Sibaud V, Lacouture ME. Pigmentary changes in patients treated with targeted anticancer agents: A systematic review and meta-analysis. J Am Acad Dermatol 2017; 77:902-910.e2. [PMID: 28918974 DOI: 10.1016/j.jaad.2017.06.044] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/15/2017] [Accepted: 06/18/2017] [Indexed: 01/13/2023]
Abstract
BACKGROUND The discovery of signaling networks that drive oncogenic processes has led to the development of targeted anticancer agents. The burden of pigmentary adverse events from these drugs is unknown. OBJECTIVE To conduct a systematic review and meta-analysis of published clinical trials and determine the incidence and risk of development of targeted therapy-induced pigmentary changes. METHODS A comprehensive search was conducted to identify studies reporting targeted therapy-induced pigmentary changes. The incidence and relative risk were calculated. Case reports and series were reviewed to understand clinical characteristics. RESULTS A total of 8052 patients from 36 clinical trials were included. The calculated overall incidences of targeted cancer therapy-induced all-grade pigmentary changes in the skin and hair were 17.7% (95% confidence interval [CI], 11.9-25.4) and 21.5% (95% CI, 14.9-30.1), respectively. The relative risk of all-grade pigmentary changes of skin and hair were 93.7 (95% CI, 5.86-1497.164) and 20.1 (95% CI, 8.35-48.248). Across 53 case reports/series (N = 75 patients), epidermal growth factor receptor and breakpoint cluster region-abelson inhibitors were the most common offending agents. LIMITATIONS Potential under-reporting and variability in oncologists reporting these events. CONCLUSION There is a significant risk of development of pigmentary changes during treatment with targeted anticancer therapies. Appropriate counseling and management are critical to minimize psychosocial impairment and deterioration in quality of life.
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Affiliation(s)
- Julia Dai
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Dermatology, Stanford University, Stanford, California
| | - Viswanath R Belum
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shenhong Wu
- Division of Medical Oncology, Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York; Division of Hematology and Oncology, Department of Medicine, Northport Veterans Administration Medical Center, Northport, New York
| | - Vincent Sibaud
- Department of Dermatology, Institut Claudius Regaud-Institut Universitaire du Cancer, Toulouse Oncopole, France
| | - Mario E Lacouture
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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De Souza K, Atabani S, Madhusudan S. Precision medicine in gastric cancer: where are we now? EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017. [DOI: 10.1080/23808993.2017.1357431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Karen De Souza
- Department of Oncology, Nottingham University Hospitals, Nottingham, UK
| | - Suha Atabani
- Department of Oncology, Nottingham University Hospitals, Nottingham, UK
| | - Srinivasan Madhusudan
- Department of Oncology, Nottingham University Hospitals, Nottingham, UK
- Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
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Abstract
Antiangiogenesis therapy is one of only 2 biologically targeted approaches shown to improve overall survival over standard of care in advanced adenocarcinoma of the stomach or gastroesophageal junction (GEJ). Therapeutic targeting of vascular endothelial growth factor receptor 2 improves overall survival in patients with previously treated advanced gastric/GEJ adenocarcinoma. No antiangiogenesis therapy has demonstrated an overall survival benefit in patients with chemo-naïve or resectable esophagogastric cancer or in patients whose tumors arise from the esophagus. Promising ongoing clinical investigations include the combination of antiangiogenesis therapy with immune checkpoint inhibition and anti-human epidermal growth factor receptor 2 therapy.
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Affiliation(s)
- Zhaohui Jin
- Department of Medical Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Harry H Yoon
- Department of Medical Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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47
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Panarese I, De Vita F, Ronchi A, Romano M, Alfano R, Di Martino N, Zito Marino F, Ferraraccio F, Franco R. Predictive biomarkers along gastric cancer pathogenetic pathways. Expert Rev Anticancer Ther 2017; 17:417-425. [PMID: 28277834 DOI: 10.1080/14737140.2017.1301207] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Gastric cancer is the second leading cause of cancer all over the world. Unfortunately, several gastric cancers are diagnosed in an advanced stage and chemotherapy and/or target therapies remain the only options to treat patients. Areas covered: Herein we evaluate the new molecular proposal of gastric cancer classification, offering the possibility to recognize different pathogenetic mechanisms and molecular biomarkers potentially useful for target therapies. Expert commentary: The possibility of introducing new specific tests for identification of molecular biomarkers critical for targeted therapies response represents the new frontier in the selection of gastric cancer patients to improve their survival. Besides HER2, already used in clinical settings as a target biomarker for biological therapy in gastric cancer patients with tissue cancer cells overexpressing HER2, other promising target biomarkers which are deregulated in gastric cancer, such as MET and FGFR, could be identified in tissue and then used for therapeutic purposes. In addition immunotherapy represents the most promising possibility of advanced gastric cancer treatment. In particular, as in other solid tumors, PD-1/PDL1 pathway has emerged in several clinical trials as an interesting therapeutic target.
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Affiliation(s)
- Iacopo Panarese
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Ferdinando De Vita
- b Division of Medical Oncology, Department of Internal and Experimental Medicine 'F. Magrassi' , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Andrea Ronchi
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Marco Romano
- c Division of Hepatogastroenterology, Department of Clinical and Experimental Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Roberto Alfano
- d General Surgery Unit, Department of Anesthesiology , Surgery and Emergency, Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Natale Di Martino
- e Department of Internal Medicine , Surgical, Neurological Metabolic Disease and Geriatric Medicine, Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Federica Zito Marino
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy.,f Pathology Unit, Istituto dei tumori 'Fondazione G. Pascale'
| | - Francesca Ferraraccio
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Renato Franco
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
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Narita Y, Muro K. Challenges in molecular targeted therapy for gastric cancer: considerations for efficacy and safety. Expert Opin Drug Saf 2017; 16:319-327. [PMID: 27976952 DOI: 10.1080/14740338.2017.1273348] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The Cancer Genome Atlas Research Network recently proposed a molecular classification for gastric cancer (GC) into four subtypes based on comprehensive evaluation. While the mechanisms of molecular targeted therapies in GC were confirmed by multiple clinical studies, only a limited number of therapeutics for GC have been approved to date. Areas covered: In this systematic review of the available literature, we discuss the completed and ongoing clinical trials of molecular targeted therapies in patients with GC, with a focus on their efficacy and safety profiles. Expert opinion: Results of recent studies clearly demonstrated that trastuzumab and ramucirumab, monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), respectively, improved overall survival (OS) in GC with manageable safety profiles. Careful surveillance of ongoing clinical trials and timely profiling and monitoring of genetic signatures are imperative to establish a strong foundation for precision medicine in GC.
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Affiliation(s)
- Yukiya Narita
- a Department of Clinical Oncology , Aichi Cancer Center Hospital , Nagoya , Japan
| | - Kei Muro
- a Department of Clinical Oncology , Aichi Cancer Center Hospital , Nagoya , Japan
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Mizrak Kaya D, Harada K, Shimodaira Y, Amlashi FG, Lin Q, Ajani JA. Advanced gastric adenocarcinoma: optimizing therapy options. Expert Rev Clin Pharmacol 2017; 10:263-271. [PMID: 28094573 DOI: 10.1080/17512433.2017.1279969] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Gastric adenocarcinoma (GAC) is the fifth most common cancer and third leading cause of cancer related mortality worldwide. When localized, cure is achievable with surgery and adjunctive therapies in some patients, however, once advanced, GAC is not a curable condition. Only two targeted agents (trastuzumab and ramucirumab) have been approved and apatinib was approved only in China. Because of the heterogeneous nature of GAC, it is not possible to assess a standard therapeutic approach. Areas covered: In this review, we aimed to describe the optimal systemic therapy regimens for advanced GAC. A literature search was performed to identify all phase II-III studies about advanced GAC from PubMed, clinicaltrials.gov, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) websites. Expert commentary: A combination of a platinum compound and a fluoropyrimidine is ideal as first line therapy. Trastuzumab should be added if the tumor is HER2 positive. In the second line setting, paclitaxel/ramucirumab is preferred over ramucirumab alone. Recently, two similar molecular classifications for GAC have been proposed. A better understanding of molecular and immune biology of GAC could identify new therapeutic targets.
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Affiliation(s)
- Dilsa Mizrak Kaya
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Kazuto Harada
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Yusuke Shimodaira
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Fatemeh G Amlashi
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Quan Lin
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jaffer A Ajani
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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Sun ZQ, Yan G, Ge YX, Li J, Jin LF, Xie ZH, Zhao P. Can low-dose CT perfusion imaging accurately assess response of advanced gastric cancer with neoadjuvant chemotherapy? JOURNAL OF X-RAY SCIENCE AND TECHNOLOGY 2017; 25:981-991. [PMID: 28697579 DOI: 10.3233/xst-17271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
PURPOSE To explore the value of low-dose CT perfusion imaging (LDCTPI) technology and its perfusion parameters in assessing response of neoadjuvant chemotherapy (NAC) in patients with advanced gastric cancer (AGC). METHODS Thirty patients with AGC were studied prospectively by LDCTPI to measure two parameters including blood flow (BF) and blood volume (BV) of tumor area before and after chemotherapy, respectively. All of the patients received two courses of NAC and surgical resection of gastric tumor within one week after chemotherapy, and then obtained the result of postoperative pathology response for chemotherapy. The comparisons of BF and BV values of AGC before and after chemotherapy were analyzed by paired-samples t-test, respectively; and the correlations between BF as well as BV decrease rates after NAC and the pathology response grade were analyzed by Spearman statistical test. Thirty patients were divided into effective and ineffective groups according to different pathology response grade. Comparisons of BF as well as BV decrease rates between effective and ineffective groups were analyzed by independent-samples t-test, respectively. Receiver operating characteristic (ROC) curves were used to determine the cutoff values of BF and BV decrease rates as evaluation indicators of AGC after NAC and calculate area under the curve (AUC). RESULTS There were significant differences in BF and BV values of AGC between before and after NAC (p < 0.001), respectively, and there were obvious correlations between BF as well as BV decrease rates and pathology response grade (r = 0.660, p < 0.001; r = 0.706, p < 0.001), respectively. There were also significant differences in BF and BV decrease rates of AGC between effective and ineffective groups (P = 0.001), respectively. If BF decrease rate of 12.1% (AUC was 0.816, P = 0.005) was used as the cutoff value for chemotherapy effectiveness of AGC, the sensitivity of 82% and specificity of 84% were achieved, and if BV decrease rate of 32.8% (AUC was 0.844, P = 0.002) was used as the cutoff value for chemotherapy effectiveness of AGC, the sensitivity of 82% and specificity of 89% were achieved. CONCLUSIONS BF and BV decrease rates have potential to be used as effective indicators to assess chemotherapy efficacy of AGC from the hemodynamics.
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Affiliation(s)
- Zong-Qiong Sun
- Department of Radiology, Affiliated Hospital of Jiangnan University, The Forth People's Hospital of Wuxi City, Wuxi, Jiangsu, China
| | - Gen Yan
- Department of Radiology, Affiliated Hospital of Jiangnan University, The Forth People's Hospital of Wuxi City, Wuxi, Jiangsu, China
| | - Yu-Xi Ge
- Department of Radiology, Affiliated Hospital of Jiangnan University, The Forth People's Hospital of Wuxi City, Wuxi, Jiangsu, China
| | - Jie Li
- Department of Intervention, Affiliated Hospital of Jiangnan University, The Forth People's Hospital of Wuxi City, Wuxi, Jiangsu, China
| | - Lin-Fang Jin
- Department of Pathology, Affiliated Hospital of Jiangnan University, The Forth People's Hospital of Wuxi City, Wuxi, Jiangsu, China
| | - Zhi-Hui Xie
- Department of Surgical Gastroenterology, Affiliated Hospital of Jiangnan University, The Forth People's Hospital of Wuxi City, Wuxi, Jiangsu, China
| | - Peng Zhao
- Departments of Neuroscience, Anatomy, Histology, and Embryology, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
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