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Wang N, Li D, Zhang T, Pachai MR, Cho WH, Khudoynazarova MN, Schoeps DM, Bao Y, Liu M, Tang L, Yelena J, Chi P, Chen Y. Loss of Kmt2c / d promotes gastric cancer initiation and confers vulnerability to mTORC1 inhibition and anti-PD1 immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.27.645747. [PMID: 40236091 PMCID: PMC11996406 DOI: 10.1101/2025.03.27.645747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
KMT2C and KMT2D ( KMT2C/D ) are frequently mutated in gastric adenocarcinoma, yet their function in cancer initiation remains poorly understood. In this study, based on the observation that loss-of-function mutations of KMT2C and KMT2D are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models to selectively knock out Kmt2c and Kmt2d in gastric epithelial cells with Tmprss2-CreER T2 . Through histological staining and single-cell RNA sequencing, we observed that Kmt2c/d loss led to nuclear dysplasia and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks post Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human gastric adenocarcinoma. Kmt2c/d knockout reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering sensitivity to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTROC1 inhibition and anti-PD1 immunotherapy significantly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c / d loss in gastric cancer initiation and suggest the potential therapeutic strategies for KMT2C/D -deficient gastric cancer.
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Bonfill Cosp X, Savall-Esteve O, Bracchiglione J, Requeijo C, Santero M. Mismatch between evidence and related clinical recommendations about the treatment of advanced esophageal cancer patients with anticancer drugs: A critical historical review. J Cancer Policy 2025; 44:100580. [PMID: 40147630 DOI: 10.1016/j.jcpo.2025.100580] [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: 07/04/2024] [Revised: 02/19/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
PURPOSE to analyze the most robust research and recommendations that have informed the potential superiority of treatments with anticancer drugs over any type of supportive care for advanced esophageal cancer (EC). METHODS We conducted a critical historical review. First, we identified randomized clinical trials (RCTs) from a previous scoping review conducted by our research group, ASTAC, updating the search strategy. Second, we searched for the most important and recognized international clinical practice guidelines (CPGs) in advanced EC. Finally, we performed a systematic document analysis to compare whether the recommendations proposed in the CPGs were supported by the previously identified relevant evidence. RESULTS We identified and assessed 15 RCTs and 11 CPGs from ESMO (eight), ASCO (two), and NICE (one) published over the last 40 years. There is a clear mismatch between these guidelines' recommendations and the available RCTs regarding the efficacy of anticancer drugs compared to best supportive care (BSC). CONCLUSION There is a lack of consistent evidence to support the treatment of advanced EC patients with anticancer drugs, and a notable mismatch exists between the available evidence and the recommendations made by relevant CPGs. As a result, these guidelines may be biased in favoring the use of anticancer drugs over supportive care and in consequence it is advisable to be very prudent when proposing systemic treatments to patients with advanced EC. Further rigorous and independent research is needed to better evaluate the true benefits of anticancer treatments in advanced EC and to update the CPGs accordingly.
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Affiliation(s)
- Xavier Bonfill Cosp
- Iberoamerican Cochrane Centre, Barcelona, Spain; Universitat Autònoma Barcelona (UAB), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
| | - Olga Savall-Esteve
- Iberoamerican Cochrane Centre, Barcelona, Spain; Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
| | - Javier Bracchiglione
- Iberoamerican Cochrane Centre, Barcelona, Spain; Universitat Autònoma Barcelona (UAB), Barcelona, Spain; Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
| | - Carolina Requeijo
- Iberoamerican Cochrane Centre, Barcelona, Spain; Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
| | - Marilina Santero
- Iberoamerican Cochrane Centre, Barcelona, Spain; Universitat Autònoma Barcelona (UAB), Barcelona, Spain; Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain.
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Meade A, Santero M, Savall-Esteve O, Bracchiglione J, Leache L, Selva A, Macias I, Cerdà P, Bonfill Cosp X. Immunotherapy or Targeted Therapy Versus Best Supportive Care for Advanced Gastric Cancer: A Systematic Review and Meta-analysis of Randomized Trials. J Gastrointest Cancer 2025; 56:75. [PMID: 40032744 PMCID: PMC11876278 DOI: 10.1007/s12029-024-01155-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2024] [Indexed: 03/05/2025]
Abstract
PURPOSE To assess the efficacy and safety of non-chemotherapy anticancer drugs (immunotherapy or targeted therapy) compared to best supportive care (BSC) or placebo for the treatment of advanced gastric cancer (GC). METHODS Systematic review of randomized controlled trials (RCTs) searching (May 2022) MEDLINE, EMBASE, CENTRAL, Epistemonikos, ClinicalTrials.gov, and PROSPERO. Certainty of evidence was evaluated following GRADE. RESULTS Six RCTs included. Targeted therapies likely result in a slight increase in overall survival (OS) (HR 0.84, 95% CI 0.75, 0.93; moderate certainty) and progression-free survival (PFS) (HR 0.52, 95% CI 0.43, 0.62; moderate certainty). Toxicity had a slightly increased risk (RR 1.19, 95% CI 0.95, 1.48; low certainty). Immunotherapy also showed a likely improvement in PFS (HR 0.60, 95% CI 0.49, 0.73; moderate certainty), while toxicity showed a likely higher risk (RR 2.72, 95% CI 1.24, 5.94; moderate certainty). However, benefits in survival translated to time gains of slightly over a month for OS and less than a month for PFS. No data were reported on performance status (PS), hospital admissions, or quality of life (QoL). CONCLUSIONS Our study suggests some survival benefits with low toxicity from these treatments, but gains are marginal. Uncertainties persist regarding their impact on QoL and outcomes for patients with poor PS. Caution is advised in treatment selection for advanced GC patients, who should actively participate in decision-making. Future research should include diverse patient populations and assess patient-centered outcomes with consistent comparator groups for BSC. TRIAL REGISTRATION The study protocol was registered in OSF ( https://doi.org/10.17605/OSF.IO/7CHX6 ) on 2022-04-01.
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Affiliation(s)
- Adriana Meade
- Iberoamerican Cochrane Centre, Institut Reserca Sant Pau (IR Sant Pau), Barcelona, Spain
| | - Marilina Santero
- Iberoamerican Cochrane Centre, Institut Reserca Sant Pau (IR Sant Pau), Barcelona, Spain.
- Autonomous University of Barcelona, Barcelona, Spain.
| | - Olga Savall-Esteve
- Iberoamerican Cochrane Centre, Institut Reserca Sant Pau (IR Sant Pau), Barcelona, Spain
- Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Javier Bracchiglione
- Iberoamerican Cochrane Centre, Institut Reserca Sant Pau (IR Sant Pau), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile
- CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Leire Leache
- Unit of Innovation and Organization, Navarre Health Service, Pamplona, Spain
- Navarre Institute of Health Research, Pamplona, Spain
| | - Anna Selva
- Autonomous University of Barcelona, Barcelona, Spain
- Institute of Research and Innovation Parc Tauli, Sabadell, Spain
- Corporació Sanitària Parc Taulí, Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | | | - Paula Cerdà
- Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Xavier Bonfill Cosp
- Iberoamerican Cochrane Centre, Institut Reserca Sant Pau (IR Sant Pau), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
- Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
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Fan P, Huang YJ, Xie XY, Wang LH, Liu B, Wang DR. ALKBH5 knockdown suppresses gastric cancer progression by reducing the expression of long non-coding RNA TUG1. Toxicol Res (Camb) 2025; 14:tfae209. [PMID: 39830887 PMCID: PMC11741680 DOI: 10.1093/toxres/tfae209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 08/29/2024] [Indexed: 01/22/2025] Open
Abstract
Purpose This study aimed to explore the relationship between m6A demethylase ALKBH5 and long noncoding RNA TUG1 (TUG1), as well as their effects on proliferation, migration, and angiogenesis in gastric cancer (GC) cells. Methods The Cancer Genome Atlas (TCGA) database was utilized to analyze the relative expression levels of ALKBH5, TUG1, and vascular endothelial growth factor A (VEGFA). Survival analyses of TUG1, ALKBH5, and VEGFA were performed using the Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier databases. The binding sites of TUG1 and ALKBH5 were predicted using the Annolnc2 database. The correlation between ALKBH5 and TUG1 expression was analyzed using the GEPIA database. Subsequently, small interfering RNA (siRNA) targeting ALKBH5 and TUG1 was transfected into SGC-7901 cells, and functional studies were conducted using quantitative real-time polymerase chain reaction (qRT-PCR), CCK-8 assays, colony formation assays, transwell assays, and angiogenesis assays. Results Bioinformatics analysis indicated that ALKBH5, TUG1, and VEGFA were highly expressed in gastric cancer tissues and exhibited a positive correlation. Survival analysis revealed that high expression levels of ALKBH5, TUG1, and VEGFA were significantly associated with poor prognosis in gastric cancer patients. Binding sites for TUG1 and ALKBH5 were identified. Functional experiments demonstrated that the knockdown of ALKBH5 resulted in the downregulation of TUG1, which subsequently reduced the proliferation, invasion, migration, and angiogenesis of gastric cancer cells. Conclusion The m6A demethylase ALKBH5 promotes gastric cancer progression by erasing the methylation modification of TUG1 and increasing TUG1 expression. This finding provides a new perspective for the treatment and prognosis assessment of gastric cancer.
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Affiliation(s)
- Peng Fan
- Gastrointestinal Center, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
- Gastrointestinal Surgery, Huaian Cancer Hospital, No. 6, Beijing RD West, Huaiyin District, Huai’an, Jiangsu 223200, China
- General Surgery Institute of Yangzhou, Yangzhou University, 88 South Daxue Road, Yangzhou, Jiangsu 225001, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
| | - Yu-jie Huang
- Department of Endocrinology, Huaian Cancer Hospital, No. 6, Beijing RD West, Huaiyin District, Huai’an, Jiangsu 223200, China
| | - Xiang-yu Xie
- Gastrointestinal Surgery, Huaian Cancer Hospital, No. 6, Beijing RD West, Huaiyin District, Huai’an, Jiangsu 223200, China
| | - Liu-hua Wang
- Gastrointestinal Center, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, 88 South Daxue Road, Yangzhou, Jiangsu 225001, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
| | - Bin Liu
- Gastrointestinal Center, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, 88 South Daxue Road, Yangzhou, Jiangsu 225001, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
| | - Dao-rong Wang
- Gastrointestinal Center, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
- General Surgery Institute of Yangzhou, Yangzhou University, 88 South Daxue Road, Yangzhou, Jiangsu 225001, China
- Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, West Nantong Road, Yangzhou, Jiangsu 225001, China
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Wu LW, Jang SJ, Shapiro C, Fazlollahi L, Wang TC, Ryeom SW, Moy RH. Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics. Target Oncol 2024; 19:845-865. [PMID: 39271577 PMCID: PMC11557641 DOI: 10.1007/s11523-024-01097-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 09/15/2024]
Abstract
Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.
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Affiliation(s)
- Lawrence W Wu
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, Room 956, New York, NY, 10032, USA
| | - Sung Joo Jang
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Cameron Shapiro
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Sandra W Ryeom
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Ryan H Moy
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, Room 956, New York, NY, 10032, USA.
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Li W, Wei J, Cheng M, Liu M. Unveiling promising targets in gastric cancer therapy: A comprehensive review. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200857. [PMID: 39280587 PMCID: PMC11396074 DOI: 10.1016/j.omton.2024.200857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Gastric cancer (GC) poses a significant global health challenge, ranking fifth in incidence and third in mortality among all malignancies worldwide. Its insidious onset, aggressive growth, proclivity for metastasis, and limited treatment options have contributed to its high fatality rate. Traditional approaches for GC treatment primarily involve surgery and chemotherapy. However, there is growing interest in targeted therapies and immunotherapies. This comprehensive review highlights recent advancements in GC targeted therapy and immunotherapy. It delves into the mechanisms of various strategies, underscoring their potential in GC treatment. Additionally, the review evaluates the efficacy and safety of relevant clinical trials. Despite the benefits observed in numerous advanced GC patients with targeted therapies and immunotherapies, challenges persist. We discuss pertinent strategies to overcome these challenges, thereby providing a solid foundation for enhancing the clinical effectiveness of targeted therapies and immunotherapies.
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Affiliation(s)
- Wenke Li
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Jing Wei
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Mo Cheng
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Ming Liu
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
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Zhang L, Yang J, Huang Y, You T, Huang Q, Shen X, Xue X, Feng S. Comprehensive landscape of gastric cancer-targeted therapy and identification of CSNK2A1 as a potential target. Heliyon 2024; 10:e36205. [PMID: 39253198 PMCID: PMC11382053 DOI: 10.1016/j.heliyon.2024.e36205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 08/11/2024] [Accepted: 08/12/2024] [Indexed: 09/11/2024] Open
Abstract
Objective To conduct a comprehensive analysis of the landscape of gastric cancer (GC)-targeted therapy clinical trials and identify potential therapeutic targets. Methods A systematic search and analysis of the Cochrane Central Register of Controlled Trials (CENTRAL) was performed to retrieve all GC clinical trials published up to June 30, 2022. Approved therapeutic targets for 11 common cancers were compiled and analyzed. The role of CSNK2A1 in GC was investigated using bioinformatics tools such as GEPIA, KMPLOT, SangerBox, STRING, ACLBI, and TIMER. Four gastric cancer cell lines (AGS, HGC, MGC, BGC) and one normal gastric mucosa cell line (GES-1) were utilized to assess the sensitivity to the CSNK2A1 inhibitor CX-4945. Quantitative real-time polymerase chain reaction (qPCR) was employed to quantify the cellular expression of CSNK2A1. Cellular apoptosis was evaluated using flow cytometry and Western blot analysis. Results The failure rate of GC randomized controlled clinical trials (RCTs) was strikingly high, accounting for 74.29 % (26/35) of the trials. Among the 35 approved targets in 11 different cancers, 13 targets were rigorously evaluated and identified as potential therapeutic targets for GC. Bioinformatics analysis revealed that CSNK2A1 is closely associated with multiple biological characteristics in GC, and its increased expression correlated significantly with enhanced sensitivity to CX-4945 treatment. Flow cytometry and Western blot analysis consistently demonstrated concentration-dependent apoptosis induced by CX-4945 in GC cell lines. Conclusions The high failure rate of GC clinical trials highlights the need for a more scientific and precise approach in target identification and clinical trial design. CSNK2A1 emerges as a promising therapeutic target for GC, and its expression level could potentially serve as a biomarker for predicting sensitivity to CX-4945 treatment. Further research is warranted to elucidate the underlying molecular mechanisms and validate the clinical significance of CSNK2A1 in GC therapy.
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Affiliation(s)
- Liang Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Jiaqi Yang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Yingpeng Huang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Tao You
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Qunjia Huang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Xiangyang Xue
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Shiyu Feng
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-Related Pathogens and Immunity, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
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Naher SK, Mercieca-Bebber R, Siu D, Stockler MR, Kiely BE, Grimison P. Estimating survival scenarios in advanced or metastatic gastric and oesophageal adenocarcinoma: a systematic review of randomized-controlled trials. Curr Med Res Opin 2024; 40:1357-1367. [PMID: 38961804 DOI: 10.1080/03007995.2024.2376129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND We aimed to summarize survival data from RCTs in patients with GO adenocarcinoma; estimate and explain worst-, typical-, and best-case-scenarios of survival time; and determine if simple multiples of median overall survival (mOS) could estimate these percentiles. METHODS We systematically searched RCTs of systemic therapies for GO adenocarcinoma published 2000-2022. The following key percentiles were extracted from overall survival curves: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We tested if these percentiles could be estimated by simple multiples of mOS: 0.25 of the median for the 90th percentile, 0.5 for the 75th, 2 for the 25th, and 3 for the 10th. RESULTS We identified 44 trials (22,447 participants). For first line chemotherapy and immunotherapy combined (CI) trials (n = 3) worst-to-best case survival time ranged from 4 months to not reached, compared to 3-30 months for other trials (n = 27) and 1-23 months for subsequent lines (n = 14). Simple multiples of mOS accurately estimated the following survival percentiles: 90th (n = 3/3 trials), 75th (n = 3/3), and 25th (n = 2/3) in first line CI trials. In other first line trials, the mOS accurately estimated the 90th survival percentile in n = 22/27 trials, 75th percentile in n = 26/27, 25th percentile in 27/27 trials, and 10th percentile in 22/27 trials. Simple multiples of the mOS accurately predicted the 90th, 75th, 25th, and 10th survival percentiles in the majority of trials of second and subsequent lines apart from chemotherapy and immunotherapy only trials. CONCLUSION We provide realistic, evidence-based prognostic information as scenarios for survival time which can inform clinical decision-making. Simple multiples of the mOS accurately estimated the percentiles for most groups.
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Affiliation(s)
- Sayeda K Naher
- National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC), University of Sydney, Camperdown, NSW, Australia
- Illawarra and Shoalhaven Local Health District, Warrawong, NSW, Australia
| | - Rebecca Mercieca-Bebber
- National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC), University of Sydney, Camperdown, NSW, Australia
| | - Derrick Siu
- National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC), University of Sydney, Camperdown, NSW, Australia
| | - Martin R Stockler
- National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC), University of Sydney, Camperdown, NSW, Australia
| | - Belinda E Kiely
- National Health and Medical Research Council (NHMRC) Clinical Trials Centre (CTC), University of Sydney, Camperdown, NSW, Australia
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Qureshi Z, Jamil A, Fatima E, Altaf F, Siddique R, Shah S. Pembrolizumab in combination with trastuzumab for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer. Ann Med Surg (Lond) 2024; 86:4647-4656. [PMID: 39118760 PMCID: PMC11305801 DOI: 10.1097/ms9.0000000000002305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/14/2024] [Indexed: 08/10/2024] Open
Abstract
Introduction Gastric cancer remains a challenging malignancy with a high global mortality rate. Recent advances in targeted therapy and immunotherapy have shown promise in improving patient outcomes. This paper reviews the impact of incorporating targeted agents such as trastuzumab and immunotherapeutic agents like pembrolizumab into standard chemotherapy regimens for gastric cancer treatment. Methods A comprehensive analysis was conducted on pivotal clinical trials, including KEYNOTE-590, KEYNOTE-811, and ToGA, focusing on their methodologies, patient populations, treatment regimens, and outcome measures. The review also explored emerging research avenues in precision medicine, particularly genomic sequencing and biomarker identification. Aim To assess the efficacy and survival benefits of adding trastuzumab and pembrolizumab to standard chemotherapy in the treatment of gastric cancer and to outline future directions in gastric cancer research. Results Including trastuzumab and pembrolizumab in treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive and PD-L1-expressing gastric cancers significantly improved progression-free and overall survival rates compared to chemotherapy alone. These findings highlight the potential of personalized therapy in enhancing treatment outcomes. Furthermore, ongoing research into the gastric cancer microenvironment and the role of the microbiome suggests novel targets for future therapeutic interventions. Conclusion The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in gastric cancer treatment, moving towards more personalized and effective regimens.
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Affiliation(s)
- Zaheer Qureshi
- The Frank H. Netter M.D. School of Medicine at Quinnipiac University, Bridgeport, CT
| | - Abdur Jamil
- Department of Medicine, Samaritan Medical Centre, Watertown, NY
| | - Eeshal Fatima
- Department of Medicine, Services Institute of Medical Sciences, Lahore, Pakistan
| | - Faryal Altaf
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/BronxCare Health System, New York, NY, USA
| | | | - Shivendra Shah
- Department of Medicine, Nepalgunj Medical College, Chisapani, Nepal
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Santero M, Meade AG, Selva A, Savall-Esteve O, Bracchiglione J, Macías I, Leache L, Cerdà P, Bonfill Cosp X. Utilising systematic reviews to assess potential overtreatment and claim for better evidence-based research: an analysis of anticancer drugs versus supportive care in advanced esophageal cancer. Syst Rev 2024; 13:186. [PMID: 39026378 PMCID: PMC11256491 DOI: 10.1186/s13643-024-02594-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/20/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Highlighting the identified gaps in evidence-based research concerning advanced esophageal cancer (EC) treatment and care, this review evaluates the efficacy and safety of anticancer drugs compared to supportive care for advanced EC patients, aiming to assess the appropriateness of usual treatments and identify the gaps that need to be filled with primary research. METHODS We searched (May 2022) MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Epistemonikos, and trial registries (ClinicalTrials.gov and PROSPERO) for randomised controlled trials (RCTs) comparing anticancer drugs (chemotherapy, immunotherapy, or biological/targeted therapy) with supportive care in advanced EC. The results were summarised using GRADE summary of finding tables. RESULTS We included 15 RCTs. Most studies did not have a special focus on EC, did not detail the treatment lines in all patients, and did not evaluate all outcomes. Anticancer drugs may result in a slight increase in overall survival (OS) (HR 0.78; 95% CI 0.71, 0.86; MD 0.83 months) and better progression-free survival (PFS) (HR 0.56 95% CI 0.49, 0.64, MD 0.68 months), but also may increase toxicity (RR 1.37; 95% CI 1.13, 1.65), without a significant improvement in quality of life. The certainty of evidence was low or very low due to indirectness of results and lack of specific focus on EC in some studies. CONCLUSION RCTs on advanced EC lack specificity, detailed treatment line information, and evaluation of all relevant outcomes. Moreover, when they find any benefit, this is negligible. Therefore, the certainty to justify anticancer drug treatments instead of supportive care in advanced EC is low or very low, and this information should be actively shared with affected patients. More and better RCTs should be conducted to assess whether any old or new proposed treatment for advanced EC patients provides a better balance of benefits and harms than the supportive care. SYSTEMATIC REVIEW REGISTRATION The study protocol was registered in OSF ( https://doi.org/10.17605/OSF.IO/7CHX6 ) on 2022-03-29.
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Affiliation(s)
- Marilina Santero
- Universitat Autònoma Barcelona, Barcelona, Spain.
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain.
| | - Adriana-Gabriela Meade
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain
| | - Anna Selva
- Universitat Autònoma Barcelona, Barcelona, Spain
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari, Institut d'Investigació I Innovació Parc Taulí (I3PT_CERCA), Sabadell, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Olga Savall-Esteve
- Universitat Autònoma Barcelona, Barcelona, Spain
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain
| | - Javier Bracchiglione
- Universitat Autònoma Barcelona, Barcelona, Spain
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile
- CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Ismael Macías
- Servicio Oncología Médica, Hospital de Sabadell-Corporació Sanitària Parc Taulí, Sabadell, Barcelona, Spain
| | - Leire Leache
- Unit of Innovation and Organization, Navarre Health Service, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Paula Cerdà
- Universitat Autònoma Barcelona, Barcelona, Spain
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain
- Hospital de La Santa Creu I Sant Pau, Barcelona, Spain
| | - Xavier Bonfill Cosp
- Universitat Autònoma Barcelona, Barcelona, Spain
- Iberoamerican Cochrane Centre, Institut de Recerca Sant Pau (IR, SANT PAU), Barcelona, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
- Hospital de La Santa Creu I Sant Pau, Barcelona, Spain
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11
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Wang J, Qu J, Hou Q, Huo X, Zhao X, Chang L, Xu C. Strategies for the Isolation and Identification of Gastric Cancer Stem Cells. Stem Cells Int 2024; 2024:5553852. [PMID: 38882596 PMCID: PMC11178399 DOI: 10.1155/2024/5553852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 04/18/2024] [Accepted: 05/07/2024] [Indexed: 06/18/2024] Open
Abstract
Gastric cancer stem cells (GCSCs) originate from both gastric adult stem cells and bone marrow cells and are conspicuously present within the histological milieu of gastric cancer tissue. GCSCs play pivotal and multifaceted roles in the initiation, progression, and recurrence of gastric cancer. Hence, the characterization of GCSCs not only facilitates precise target identification for prospective therapeutic interventions in gastric cancer but also has significant implications for targeted therapy and the prognosis of gastric cancer. The prevailing techniques for GCSC purification involve their isolation using surface-specific cell markers, such as those identified by flow cytometry and immunomagnetic bead sorting techniques. In addition, in vitro culture and side-population cell sorting are integral methods in this context. This review discusses the surface biomarkers, isolation techniques, and identification methods of GCSCs, as well as their role in the treatment of gastric cancer.
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Affiliation(s)
- Jianhua Wang
- Shaanxi Provincial Key Laboratory of Infection and Immune Diseases Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Second Department of General Surgery Shaanxi Provincial People's Hospital, Xi'an 710068 710068, China
- Department of Graduate School Yan'an University, Yan'an 716009, China
| | - Jie Qu
- Second Department of General Surgery Shaanxi Provincial People's Hospital, Xi'an 710068 710068, China
- Department of Graduate School Yan'an University, Yan'an 716009, China
| | - Qiang Hou
- Second Department of General Surgery Shaanxi Provincial People's Hospital, Xi'an 710068 710068, China
- Department of Graduate School Yan'an University, Yan'an 716009, China
| | - Xueping Huo
- Shaanxi Provincial Key Laboratory of Infection and Immune Diseases Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Shaanxi Engineering Research Center of Cell Immunology Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Xiangrong Zhao
- Shaanxi Provincial Key Laboratory of Infection and Immune Diseases Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Shaanxi Engineering Research Center of Cell Immunology Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Le Chang
- Shaanxi Provincial Key Laboratory of Infection and Immune Diseases Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Shaanxi Engineering Research Center of Cell Immunology Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Cuixiang Xu
- Shaanxi Provincial Key Laboratory of Infection and Immune Diseases Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Shaanxi Engineering Research Center of Cell Immunology Shaanxi Provincial People's Hospital, Xi'an 710068, China
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12
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Kırboğa KK, Rudrapal M. Feature Engineering-Assisted Drug Repurposing on Disease-Drug Transcriptome Profiles in Gastric Cancer. Assay Drug Dev Technol 2024; 22:181-191. [PMID: 38572922 DOI: 10.1089/adt.2023.141] [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] [Indexed: 04/05/2024] Open
Abstract
Gastric cancer is one of the most common and deadly types of cancer in the world. To develop new biomarkers and drugs to diagnose and treat this cancer, it is necessary to identify the differences between the transcriptome profiles of gastric cancer and healthy individuals, identify critical genes associated with these differences, and make potential drug predictions based on these genes. In this study, using two gene expression datasets related to gastric cancer (GSE19826 and GSE79973), 200 genes that were ready for machine learning were selected, and their expression levels were analyzed. The best 100 genes for the model were chosen with the permutation feature importance method, and central genes, such as SCARB1, ETV3, SPATA17, FAM167A-AS1, and MTBP, which were shown to be associated with gastric cancer, were identified. Then, using the drug repurposing method with the Connectivity Map CLUE Query tools, potential drugs such as Forskolin, Gestrinone, Cediranib, Apicidine, and Everolimus, which showed a highly negative correlation with the expression levels of the selected genes, were identified. This study provides a method to develop new approaches to diagnosing and treating gastric cancer by comparing the transcriptome profiles of patients gastric cancer and performing a feature engineering-assisted drug repurposing analysis based on cancer data.
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Affiliation(s)
- Kevser Kübra Kırboğa
- Bioengineering Department, Faculty of Engineering, Bilecik Seyh Edebali University, Bilecik, Türkiye
| | - Mithun Rudrapal
- Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research (Deemed to be University), Guntur, India
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13
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Scheck MK, Hofheinz RD, Lorenzen S. HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments. Cancers (Basel) 2024; 16:1336. [PMID: 38611014 PMCID: PMC11010911 DOI: 10.3390/cancers16071336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.
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Affiliation(s)
- Magdalena K. Scheck
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
| | - Ralf D. Hofheinz
- Mannheim Cancer Center, Universitätsklinikum Mannheim, 68167 Mannheim, Germany;
| | - Sylvie Lorenzen
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
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14
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Morgos DT, Stefani C, Miricescu D, Greabu M, Stanciu S, Nica S, Stanescu-Spinu II, Balan DG, Balcangiu-Stroescu AE, Coculescu EC, Georgescu DE, Nica RI. Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer. Int J Mol Sci 2024; 25:1848. [PMID: 38339127 PMCID: PMC10856016 DOI: 10.3390/ijms25031848] [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: 12/21/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-PI3K/AKT/mTOR-and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.
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Affiliation(s)
- Diana-Theodora Morgos
- Discipline of Anatomy, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Constantin Stefani
- Department I of Family Medicine and Clinical Base, “Dr. Carol Davila” Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Daniela Miricescu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Maria Greabu
- Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Silviu Stanciu
- Department of Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Silvia Nica
- Emergency Discipline, University Hospital of Bucharest, 050098 Bucharest, Romania;
| | - Iulia-Ioana Stanescu-Spinu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Daniela Gabriela Balan
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Andra-Elena Balcangiu-Stroescu
- Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (I.-I.S.-S.); (D.G.B.); (A.-E.B.-S.)
| | - Elena-Claudia Coculescu
- Discipline of Oral Pathology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Dragos-Eugen Georgescu
- Department of General Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 50474 Bucharest, Romania;
- Department of General Surgery, “Dr. Ion Cantacuzino” Clinical Hospital, 020475 Bucharest, Romania
| | - Remus Iulian Nica
- Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania;
- Discipline of General Surgery, Faculty of Midwifery and Nursing, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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15
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Kim IH. Emerging Targets for Systemic Treatment of Gastric Cancer: HER2 and Beyond. J Gastric Cancer 2024; 24:29-56. [PMID: 38225765 PMCID: PMC10774754 DOI: 10.5230/jgc.2024.24.e6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/17/2024] Open
Abstract
In recent years, remarkable progress has been made in the molecular profiling of gastric cancer. This progress has led to the development of various molecular classifications to uncover subtype-specific dependencies that can be targeted for therapeutic interventions. Human epidermal growth factor receptor 2 (HER2) is a crucial biomarker for advanced gastric cancer. The recent promising results of novel approaches, including combination therapies or newer potent agents such as antibody-drug conjugates, have once again brought attention to anti-HER2 targeted treatments. In HER2-negative diseases, the combination of cytotoxic chemotherapy and programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors has become the established standard of care in first-line settings. In the context of gastric cancer, potential biomarkers such as PD-L1 expression, Epstein-Barr virus, microsatellite instability, and tumor mutational burden are being considered for immunotherapy. Recently, promising results have been reported in studies on anti-Claudin18.2 and fibroblast growth factor receptor 2 treatments. Currently, many ongoing trials are aimed at identifying potential targets using novel approaches. Further investigations will be conducted to enhance the progress of these therapies, addressing challenges such as primary and acquired resistance, tumor heterogeneity, and clonal evolution. We believe that these efforts will improve patient prognoses. Herein, we discuss the current evidence of potential targets for systemic treatment, clinical considerations, and future perspectives.
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Affiliation(s)
- In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea,.
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16
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Ihlamur M, Akgul B, Zengin Y, Korkut ŞV, Kelleci K, Abamor EŞ. The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches. Curr Mol Med 2024; 24:478-494. [PMID: 37165594 DOI: 10.2174/1566524023666230509161645] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 05/12/2023]
Abstract
mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer. This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.
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Affiliation(s)
- Murat Ihlamur
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
- Department of Electronics and Automation, Biruni University, Istanbul, Turkey
| | - Busra Akgul
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Yağmur Zengin
- Biomedical Engineering Institute, Department of Biomedical Engineering, Bogazici University, Istanbul, Turkey
| | - Şenay Vural Korkut
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Yildiz Technical University, Istanbul, Turkey
| | - Kübra Kelleci
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
- Department of Medical Services and Techniques, Beykoz University, Istanbul, Turkey
| | - Emrah Şefik Abamor
- Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, Istanbul, Turkey
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17
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Liu Z, Huang H, Yu Y, Li L, Shi X, Wang F. Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology. J Cell Mol Med 2023; 27:3878-3896. [PMID: 37794689 PMCID: PMC10718161 DOI: 10.1111/jcmm.17967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/17/2023] [Accepted: 08/30/2023] [Indexed: 10/06/2023] Open
Abstract
Ellagic acid (EA) is a natural polyphenolic compound. Recent studies have shown that EA has potential anticancer properties against gastric cancer (GC). This study aims to reveal the potential targets and mechanisms of EA against GC. This study adopted methods of bioinformatics analysis and network pharmacology, including the weighted gene co-expression network analysis (WGCNA), construction of protein-protein interaction (PPI) network, receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival curve analysis, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics simulations (MDS). A total of 540 EA targets were obtained. Through WGCNA, we obtained a total of 2914 GC clinical module genes, combined with the disease database for screening, a total of 606 GC-related targets and 79 intersection targets of EA and GC were obtained by constructing Venn diagram. PPI network was constructed to identify 14 core candidate targets; TP53, JUN, CASP3, HSP90AA1, VEGFA, HRAS, CDH1, MAPK3, CDKN1A, SRC, CYCS, BCL2L1 and CDK4 were identified as the key targets of EA regulation of GC by ROC and KM curve analysis. The enrichment analysis of GO and KEGG pathways of key targets was performed, and they were mainly enriched in p53 signalling pathway, PI3K-Akt signalling pathway. The results of molecular docking and MDS showed that EA could effectively bind to 13 key targets to form stable protein-ligand complexes. This study revealed the key targets and molecular mechanisms of EA against GC and provided a theoretical basis for further study of the pharmacological mechanism of EA against GC.
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Affiliation(s)
- Zhiyao Liu
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Hailiang Huang
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Ying Yu
- Innovative Institute of Chinese Medicine and PharmacyShandong University of Traditional Chinese MedicineJinanChina
| | - Lingling Li
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Xin Shi
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
| | - Fangqi Wang
- Department of Rehabilitation MedicineShandong University of Traditional Chinese MedicineJinanChina
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18
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Dai ZT, Wu YL, Xu T, Li XR, Ji T. The role of lncRNA SNHG14 in gastric cancer: enhancing tumor cell proliferation and migration, and mechanisms of CDH2 expression. Cell Cycle 2023; 22:2522-2537. [PMID: 38193271 PMCID: PMC10936682 DOI: 10.1080/15384101.2023.2289745] [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: 01/31/2023] [Revised: 05/30/2023] [Accepted: 11/26/2023] [Indexed: 01/10/2024] Open
Abstract
LncRNAs are a class of non-coding RNAs that play an important role in regulating gene expression. However, their specific molecular mechanisms in gastric carcinogenesis and metastasis need further exploration. TCGA data showed that the expression of MFGE8, which was closely related to survival, was significantly positively correlated with lncRNA SNHG14. And moreover, the results of high-throughput sequencing and qRT-PCR showed that lncRNA SNHG14 was significantly elevated in gastric cancer. Further, in vitro functional realization showed that lncRNA SNHG14 overexpression significantly increased gastric cancer's proliferation, invasion and migration. Animal experiments also showed that lncRNA SNHG14 overexpression promoted tumorigenesis and metastasis in vivo. Mechanistically, MFGE8 activates the expression of lncRNA SNHG14, which activates the cellular EMT by stabilizing CDH2. Our study suggests that lncRNA SNHG14 could be a potential target for gastric cancer therapy.
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Affiliation(s)
- Zhou-Tong Dai
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Centre for Obstetrics and Gynaecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Life and Health Science, Wuhan University of Science and Technology, Wuhan, China
| | - Yong-Lin Wu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Xu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Rui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Teng Ji
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Centre for Obstetrics and Gynaecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Negura I, Pavel-Tanasa M, Danciu M. Regulatory T cells in gastric cancer: Key controllers from pathogenesis to therapy. Cancer Treat Rev 2023; 120:102629. [PMID: 37769435 DOI: 10.1016/j.ctrv.2023.102629] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 09/30/2023]
Abstract
Gastric cancer (GC) is a highly aggressive malignancy that remains a significant contributor to cancer-related mortality worldwide, despite a decline in incidence in recent years. Early-stage GC poses a diagnostic challenge due to its asymptomatic nature, leading to poor prognoses for most patients. Conventional treatment approaches, including chemotherapy and surgery, have shown limited efficacy in improving outcomes for GC patients. The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, yielding durable responses across various malignancies. However, the clinical benefits of ICIs in GC have been modest, underscoring the need for a comprehensive understanding of immune cell functions within the GC tumor microenvironment (TME). Regulatory T cells (Tregs), a subset of T lymphocytes, play a pivotal role in GC development and progression and serve as prognostic biomarkers for GC patients. This review aims to elucidate the multifaceted roles of Tregs in the pathogenesis, progression, and prognosis of gastric cancer, and establish their actual and future potential as therapeutic targets. By providing insights into the intricate interplay between Tregs and the TME, this review strives to stimulate further investigation and facilitate the development of targeted Treg-based therapeutic strategies for GC.
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Affiliation(s)
- Ion Negura
- Department of Pathology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Mariana Pavel-Tanasa
- Department of Immunology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania.
| | - Mihai Danciu
- Department of Pathology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
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20
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Kim JS, Kim MY, Hong S. Synergistic Effects of Metformin and Trastuzumab on HER2 Positive Gastroesophageal Adenocarcinoma Cells In Vitro and In Vivo. Cancers (Basel) 2023; 15:4768. [PMID: 37835462 PMCID: PMC10571931 DOI: 10.3390/cancers15194768] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/16/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
The incidence of HER2 amplification in advanced gastroesophageal adenocarcinoma (GC) reportedly ranges between 10% and 20%, depending on the population studied and the geographical region. Trastuzumab (Tmab) is the standard treatment for GCs with HER2 amplification. Metformin, a widely used antidiabetic drug, is an activator of AMP kinase that can affect the mTOR signaling pathway. The following GC cells were evaluated: HER2+ NCI-N87, YCC-19, YCC-38, OE19, OE33, and HER2- AGS. The effects of Tmab and metformin on these cell lines were assessed as single agents and in combination using cell viability assays, Western blotting, and xenograft models. Metformin induced phosphorylation of AMP kinase in all tested GC cells and dephosphorylation of mTOR in Tmab-sensitive GC cells. We observed that treatment with Tmab in combination with metformin induced a significant decrease in the number of colonies formed on soft agar by N87, YCC-19, YCC-38, and OE19 cells (88%, 95%, 73%, and 98%, respectively), in comparison to the number formed by control cells or cells in the single-treatment groups. No growth inhibition was detected in OE33 cells treated with Tmab alone. Combination with metformin resulted in decreased phosphorylation of HER2 and its downstream targets, AKT and ERK, in Tmab-sensitive HER2+ cells. Phospho-receptor tyrosine kinase (RTK) arrays were used to profile the phospho-proteome, which demonstrated a synergistic decrease in phosphorylation of EGFR, HER2, and HER3. Furthermore, the combination of Tmab and metformin exhibited enhanced antitumor effects in a xenograft model. Collectively, these data suggest that Tmab and metformin act synergistically in HER2+ GC cells. Since metformin is widely used and relatively non-toxic, its addition to the therapeutic regimen along with Tmab could enhance the clinical efficacy in patients with HER2+ GC.
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Affiliation(s)
- Jin-Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Mi Young Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Sungyoul Hong
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;
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21
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Fukuoka S, Koga Y, Yamauchi M, Koganemaru S, Yasunaga M, Shitara K, Doi T, Yoshino T, Kuronita T, Elenbaas B, Wahra P, Zhang H, Crowley L, Jenkins MH, Clark A, Kojima T. p70S6K/Akt dual inhibitor DIACC3010 is efficacious in preclinical models of gastric cancer alone and in combination with trastuzumab. Sci Rep 2023; 13:16017. [PMID: 37749105 PMCID: PMC10520030 DOI: 10.1038/s41598-023-40612-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 08/14/2023] [Indexed: 09/27/2023] Open
Abstract
The PI3K-Akt-mTOR (PAM) pathway is implicated in tumor progression in many tumor types, including metastatic gastric cancer (GC). The initial promise of PAM inhibitors has been unrealized in the clinic, presumably due, in part, to the up-regulation of Akt signaling that occurs when the pathway is inhibited. Here we present that DIACC3010 (formerly M2698), an inhibitor of two nodes in the PAM pathway, p70S6K and Akt 1/3, blocks the pathway in in vitro and in vivo preclinical models of GC while providing a mechanism that inhibits signaling from subsequent Akt up-regulation. Utilizing GC cell lines and xenograft models, we identified potential markers of DIACC3010-sensitivity in Her2-negative tumors, i.e., PIK3CA mutations, low basal pERK, and a group of differentially expressed genes (DEGs). The combination of DIACC3010 and trastuzumab was evaluated in Her2-positive cell lines and models. Potential biomarkers for the synergistic efficacy of the combination of DIACC3010 + trastuzumab also included DEGs as well as a lack of up-regulation of pERK. Of 27 GC patient-derived xenograft (PDX) models tested in BALB/c nu/nu mice, 59% were sensitive to DIACC3010 + trastuzumab. Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.
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Affiliation(s)
- Shota Fukuoka
- Division of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yoshikatsu Koga
- Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Kashiwa, Japan
| | - Mayumi Yamauchi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masahiro Yasunaga
- Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Toshihiko Doi
- Division of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Toshio Kuronita
- Merck Biopharma Co., Ltd. (an affiliate of Merck KGaA), Tokyo, Japan
| | - Brian Elenbaas
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Pamela Wahra
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Hong Zhang
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Lindsey Crowley
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Molly H Jenkins
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Anderson Clark
- EMD Serono Research & Development Institute, Inc. (an affiliate of Merck KGaA), Billerica, MA, USA
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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22
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Ma G, Sun Y, Cai F, Zhang M, Liang H, Deng J, Zhang R, Zhang L. DEPTOR as a novel prognostic marker inhibits the proliferation via deactivating mTOR signaling pathway in gastric cancer cells. Exp Cell Res 2023; 427:113598. [PMID: 37054772 DOI: 10.1016/j.yexcr.2023.113598] [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: 08/17/2022] [Revised: 02/15/2023] [Accepted: 04/09/2023] [Indexed: 04/15/2023]
Abstract
Aberrantly activated mTOR signaling pathway is commonly found in malignancies including gastric cancer (GC). DEPTOR, as a naturally occurred inhibitor of mTOR, functions in the pro- or anti-tumor manner depending on distinct tumor contexts. However, the roles of DEPTOR in GC remain largely unknown. In this study, DEPTOR expression was identified to be significantly decreased in GC tissues compared with matched normal gastric tissues, and reduced DEPTOR level was indicative of poor prognosis in patients. Restored DEPTOR expression inhibited the propagation in AGS and NCI-N87 cells, whose DEPTOR levels are low, via deactivating mTOR signaling pathway. Likewise, cabergoline (CAB) attenuated the proliferation in AGS and NCI-N87 cells via partially rescuing DEPTOR protein level. Targeted metabolomics analysis showed that several key metabolites, such as l-serine, significantly changed in AGS cells with DEPTOR restoration. These results revealed the anti-proliferation function of DEPTOR in GC cells, suggesting that restored DEPTOR expression using CAB may be a potential therapeutic approach for patients with GC.
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Affiliation(s)
- Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yi Sun
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Mengmeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Li Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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23
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Marilina S, Adriana M, Anna S, Roberto AD, Nicolás M, Jesús QM, Javier B, Carolina R, Josefina S, Gerardo RG, Ivan S, Gerard U, Xavier BC. Comparative analysis of systemic oncological treatments and best supportive care for advanced gastresophageal cancer: A comprehensive scoping review and evidence map. J Evid Based Med 2023; 16:216-236. [PMID: 37303304 DOI: 10.1111/jebm.12539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 05/30/2023] [Indexed: 06/13/2023]
Abstract
OBJECTIVE To identify, describe, and organize the available evidence regarding systemic oncological treatments compared to best supportive care (BSC) for advanced gastresophageal cancer. METHODS We conducted a thorough search across MEDLINE (PubMed), EMbase (Ovid), The Cochrane Library, Epistemonikos, PROSPERO, and Clinicaltrials.gov. Our inclusion criteria encompassed systematic reviews, randomized controlled trials, quasi-experimental and observational studies involving patients with advanced esophageal or gastric cancer receiving chemotherapy, immunotherapy or biological/targeted therapy compared to BSC. The outcomes included survival, quality of life, functional status, toxicity, and quality of end-of-life care. RESULTS We included and mapped 72 studies, comprising SRs, experimental and observational designs, 12 on esophageal cancer, 51 on gastric cancer, and 10 both locations. Most compared schemes including chemotherapy (47 studies), but did not report therapeutic lines. Moreover, BSC as a control arm was poorly defined, including integral support and placebo. Data favor the use of systemic oncological treatments in survival outcomes and BSC in toxicity. Data for outcomes including quality of life, functional status, and quality of end-of-life care were limited. We found sundry evidence gaps specifically in assessing new treatments such as immunotherapy and important outcomes such as functional status, symptoms control, hospital admissions, and the quality of end-life care for all the treatments. CONCLUSIONS There are important evidence gaps regarding new for patients with advanced gastresophageal cancer and the effect of systemic oncological treatments on important patient-centered outcomes beyond survival. Future research should clearly describe the population included, specifying previous treatments and considering therapeutic, and consider all patient-centered outcomes. Otherwise, it will be complex to apply research results into practice.
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Affiliation(s)
- Santero Marilina
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Meade Adriana
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Selva Anna
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT_CERCA). Univesitat Autònoma de Barcelona., Sabadell, Spain
| | - Acosta-Dighero Roberto
- Faculty of Medicine, Department of Physical Therapy, University of Chile, Santiago, Chile
| | - Meza Nicolás
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile
| | - Quintana Maria Jesús
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
- Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Bracchiglione Javier
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile
| | - Requeijo Carolina
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Salazar Josefina
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | | | - Solà Ivan
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
| | - Urrútia Gerard
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
| | - Bonfill Cosp Xavier
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), CIBER, Barcelona, Spain
- Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
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24
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Li JJ, Rogers JE, Yamashita K, Waters RE, Blum Murphy M, Ajani JA. Therapeutic Advances in the Treatment of Gastroesophageal Cancers. Biomolecules 2023; 13:biom13050796. [PMID: 37238666 DOI: 10.3390/biom13050796] [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: 04/01/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers.
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Affiliation(s)
- Jenny J Li
- Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Jane E Rogers
- Department of Pharmacy Clinical Program, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Kohei Yamashita
- Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Rebecca E Waters
- Department of Pathology, Division of Pathology/Lab Medicine, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Mariela Blum Murphy
- Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
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25
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Shin WS, Xie F, Chen B, Yu P, Yu J, To KF, Kang W. Updated Epidemiology of Gastric Cancer in Asia: Decreased Incidence but Still a Big Challenge. Cancers (Basel) 2023; 15:cancers15092639. [PMID: 37174105 PMCID: PMC10177574 DOI: 10.3390/cancers15092639] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/02/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Despite the decline in incidence and mortality rates, gastric cancer (GC) is the fifth leading cause of cancer deaths worldwide. The incidence and mortality of GC are exceptionally high in Asia due to high H. pylori infection, dietary habits, smoking behaviors, and heavy alcohol consumption. In Asia, males are more susceptible to developing GC than females. Variations in H. pylori strains and prevalence rates may contribute to the differences in incidence and mortality rates across Asian countries. Large-scale H. pylori eradication was one of the effective ways to reduce GC incidences. Treatment methods and clinical trials have evolved, but the 5-year survival rate of advanced GC is still low. Efforts should be put towards large-scale screening and early diagnosis, precision medicine, and deep mechanism studies on the interplay of GC cells and microenvironments for dealing with peritoneal metastasis and prolonging patients' survival.
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Affiliation(s)
- Wing Sum Shin
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Fuda Xie
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China
| | - Peiyao Yu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China
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26
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Alsina M, Arrazubi V, Diez M, Tabernero J. Current developments in gastric cancer: from molecular profiling to treatment strategy. Nat Rev Gastroenterol Hepatol 2023; 20:155-170. [PMID: 36344677 DOI: 10.1038/s41575-022-00703-w] [Citation(s) in RCA: 169] [Impact Index Per Article: 84.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2022] [Indexed: 11/09/2022]
Abstract
Gastric cancer and gastro-oesophageal junction cancer represent a global health-care challenge. Despite the efficacy of improved chemotherapy and surgical options, these patients still have a poor prognosis. In advanced disease, only trastuzumab and some immune checkpoint inhibitors, such as nivolumab and pembrolizumab in addition to chemotherapy, have demonstrated consistent and reliable efficacy in patients with HER2-positive and PDL1-positive tumours, respectively. In this Review, we discuss the intrinsic characteristics of gastric and gastro-oesophageal cancer from the molecular and clinical perspectives and provide a comprehensive review of previously reported and ongoing phase II and III clinical trials with targeted agents and immunotherapy in advanced and localized settings. Finally, we suggest alternative strategies to help overcome current challenges in precision medicine and to improve outcomes for these patients.
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Affiliation(s)
- Maria Alsina
- Gastrointestinal and Endocrinology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Medical Oncology Department, Hospital Universitario de Navarra (HUN), Pamplona, Spain.,Oncobiona Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Pamplona, Spain.,Oncobiona Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Marc Diez
- Gastrointestinal and Endocrinology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Medical Oncology Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain
| | - Josep Tabernero
- Gastrointestinal and Endocrinology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. .,Medical Oncology Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain.
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27
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Zhong YL, Wang PQ, Hao DL, Sui F, Zhang FB, Li B. Traditional Chinese medicine for transformation of gastric precancerous lesions to gastric cancer: A critical review. World J Gastrointest Oncol 2023; 15:36-54. [PMID: 36684050 PMCID: PMC9850768 DOI: 10.4251/wjgo.v15.i1.36] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/06/2022] [Accepted: 12/28/2022] [Indexed: 01/10/2023] Open
Abstract
Gastric cancer (GC) is a common gastrointestinal tumor. Gastric precancerous lesions (GPL) are the last pathological stage before normal gastric mucosa transforms into GC. However, preventing the transformation from GPL to GC remains a challenge. Traditional Chinese medicine (TCM) has been used to treat gastric disease for millennia. A series of TCM formulas and active compounds have shown therapeutic effects in both GC and GPL. This article reviews recent progress on the herbal drugs and pharmacological mechanisms of TCM in preventing the transformation from GPL to GC, especially focusing on anti-inflammatory, anti-angiogenesis, proliferation, and apoptosis. This review may provide a meaningful reference for the prevention of the transformation from GPL to GC using TCM.
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Affiliation(s)
- Yi-Lin Zhong
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Peng-Qian Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Dan-Li Hao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Feng Sui
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Feng-Bin Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Bing Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
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28
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Lv H, He Y, Nie C, Du F, Chen X. Adding of apatinib and camrelizumab to overcome de novo trastuzumab resistance of HER2-positive gastric cancer: A case report and literature review. Front Pharmacol 2023; 13:1067557. [PMID: 36699065 PMCID: PMC9868577 DOI: 10.3389/fphar.2022.1067557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/13/2022] [Indexed: 01/10/2023] Open
Abstract
Background: Studies confirmed that trastuzumab plus fluorouracil-based chemotherapy improves the survival to more than 1 year in human with human epidermal growth factor receptor-2 (HER2)-positive advanced gastric cancer. However, there are still a small proportion of patients who do not benefit from trastuzumab treatment. Case summary: Here, we described a case report of de novo trastuzumab resistance in HER2-positive gastric cancer. Concomitant cyclin-E1 (CCNE1) and HER2 amplification are associated with de novo trastuzumab resistance. Genomic analysis demonstrated CCNE1 amplification and TP53 mutation in a HER2-positive gastric cancer patient. This patient achieved significant survival benefit and good safety when the patient received triple regimens consisting of trastuzumab, apatinib, and camrelizumab. Conclusion: Trastuzumab plus camrelizumab plus apatinib has the potential efficacy in HER2-positive gastric cancer patients who were previously treated with trastuzumab plus chemotherapy. This may lead to a new solution to trastuzumab resistance.
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Affiliation(s)
| | | | | | | | - Xiaobing Chen
- The Affiliated Cancer Hospital of Zhengzhou University, Henan cancer hospital, Zhengzhou, China
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29
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Cao B, Zhao R, Li H, Xu X, Gao J, Chen L, Wei B. Inhibition of androgen receptor enhanced the anticancer effects of everolimus through targeting glucose transporter 12. Int J Biol Sci 2023; 19:104-119. [PMID: 36594084 PMCID: PMC9760431 DOI: 10.7150/ijbs.75106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 10/08/2022] [Indexed: 11/24/2022] Open
Abstract
Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It has been proven as a targeted drug for gastric cancer (GC) therapy. However, long-term treatment with everolimus may cause severe side effects for recipients. Decreasing the dosage and attenuating the associated risks are feasible to promote clinical translation of everolimus. This study aimed to identify the underlying mechanisms of responses to everolimus and develop novel regimens for GC treatment. Our findings proved that there was a significant dose-dependent relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was actively upregulated to counteract the anticancer effects of everolimus. GLUT12 might be overexpressed in GC. High expression of GLUT12 might be correlated with tumor progression and short survival time of GC patients. Bioinformatic analysis suggested that GLUT12 might be involved in regulating cancer development and metabolism. The experiments proved that GLUT12 significantly promoted GC growth, glycolysis and impaired the anticancer effects of everolimus. Androgen receptor (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated the promotive effects on GLUT12 expression. Both in-vitro and in-vivo experiments demonstrated that GLUT12 knockdown augmented anticancer effects of everolimus. Enzalutamide, an AR inhibitor, or AR knockdown was comparable to GLUT12 suppression. This study identified the role of the AR/GLUT12 pathway in the development of poor responses to everolimus. Interference with AR/GLUT12 pathway may serve as a promising approach to promoting the translational application of everolimus in GC therapy.
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Affiliation(s)
- Bo Cao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.,Medical School of Chinese PLA, Beijing 100853, China
| | - Ruiyang Zhao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.,Medical School of Chinese PLA, Beijing 100853, China
| | - Hanghang Li
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.,Medical School of Chinese PLA, Beijing 100853, China
| | - Xingming Xu
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Jingwang Gao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.,Medical School of Chinese PLA, Beijing 100853, China
| | - Lin Chen
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.,Medical School of Chinese PLA, Beijing 100853, China.,✉ Corresponding authors: Bo Wei, MD, PhD, Chief Doctor, Professor, Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Tel: +86-10-66938071; E-mail: ; Lin Chen, MD, PhD, Chief Doctor, Professor, Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Tel: +86-10-66938066; E-mail:
| | - Bo Wei
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.,Medical School of Chinese PLA, Beijing 100853, China.,✉ Corresponding authors: Bo Wei, MD, PhD, Chief Doctor, Professor, Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Tel: +86-10-66938071; E-mail: ; Lin Chen, MD, PhD, Chief Doctor, Professor, Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Tel: +86-10-66938066; E-mail:
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30
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Patrad E, Khalighfard S, Amiriani T, Khori V, Alizadeh AM. Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy. Cell Oncol 2022; 45:1073-1117. [PMID: 36149600 DOI: 10.1007/s13402-022-00715-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer imposes a substantial global health burden despite its overall incidence decrease. A broad spectrum of inherited, environmental and infectious factors contributes to the development of gastric cancer. A profound understanding of the molecular underpinnings of gastric cancer has lagged compared to several other tumors with similar incidence and morbidity rates, owing to our limited knowledge of the role of carcinogens in this malignancy. The International Agency for Research on Cancer (IARC) has classified gastric carcinogenic agents into four groups based on scientific evidence from human and experimental animal studies. This review aims to explore the potential comprehensive molecular and biological impacts of carcinogens on gastric cancer development and their interactions and interferences with various cellular signaling pathways. CONCLUSIONS In this review, we highlight recent clinical trial data reported in the literature dealing with different ways to target various carcinogens in gastric cancer. Moreover, we touch upon other multidisciplinary therapeutic approaches such as surgery, adjuvant and neoadjuvant chemotherapy. Rational clinical trials focusing on identifying suitable patient populations are imperative to the success of single-agent therapeutics. Novel insights regarding signaling pathways that regulate gastric cancer can potentially improve treatment responses to targeted therapy alone or in combination with other/conventional treatments. Preventive strategies such as control of H. pylori infection through eradication or immunization as well as dietary habit and lifestyle changes may reduce the incidence of this multifactorial disease, especially in high prevalence areas. Further in-depth understanding of the molecular mechanisms involved in the role of carcinogenic agents in gastric cancer development may offer valuable information and update state-of-the-art resources for physicians and researchers to explore novel ways to combat this disease, from bench to bedside. A schematic outlining of the interaction between gastric carcinogenic agents and intracellular pathways in gastric cancer H. pylori stimulates multiple intracellular pathways, including PI3K/AKT, NF-κB, Wnt, Shh, Ras/Raf, c-MET, and JAK/STAT, leading to epithelial cell proliferation and differentiation, apoptosis, survival, motility, and inflammatory cytokine release. EBV can stimulate intracellular pathways such as the PI3K/Akt, RAS/RAF, JAK/STAT, Notch, TGF-β, and NF-κB, leading to cell survival and motility, proliferation, invasion, metastasis, and the transcription of anti-apoptotic genes and pro-inflammatory cytokines. Nicotine and alcohol can lead to angiogenesis, metastasis, survival, proliferation, pro-inflammatory, migration, and chemotactic by stimulating various intracellular signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, ROS, and JAK/STAT. Processed meat contains numerous carcinogenic compounds that affect multiple intracellular pathways such as sGC/cGMP, p38 MAPK, ERK, and PI3K/AKT, leading to anti-apoptosis, angiogenesis, metastasis, inflammatory responses, proliferation, and invasion. Lead compounds may interact with multiple signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, DNA methylation-dependent, and epigenetic-dependent, leading to tumorigenesis, carcinogenesis, malignancy, angiogenesis, DNA hypermethylation, cell survival, and cell proliferation. Stimulating signaling pathways such as PI3K/Akt, RAS/RAF, JAK/STAT, WNT, TGF-β, EGF, FGFR2, and E-cadherin through UV ionizing radiation leads to cell survival, proliferation, and immortalization in gastric cancer. The consequence of PI3K/AKT, NF-κB, Ras/Raf, ROS, JAK/STAT, and WNT signaling stimulation by the carcinogenic component of Pickled vegetables and salted fish is the Warburg effect, tumorigenesis, angiogenesis, proliferation, inflammatory response, and migration.
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Affiliation(s)
- Elham Patrad
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Solmaz Khalighfard
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Taghi Amiriani
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Vahid Khori
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Breast Disease Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
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31
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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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32
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Bousset L, Gil J. Targeting senescence as an anticancer therapy. Mol Oncol 2022; 16:3855-3880. [PMID: 36065138 PMCID: PMC9627790 DOI: 10.1002/1878-0261.13312] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/12/2022] [Accepted: 08/21/2022] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anticancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one-two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.
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Affiliation(s)
- Laura Bousset
- MRC London Institute of Medical Sciences (LMS)UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS)Imperial College LondonUK
| | - Jesús Gil
- MRC London Institute of Medical Sciences (LMS)UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS)Imperial College LondonUK
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33
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Jahangiri B, Saei AK, Obi PO, Asghari N, Lorzadeh S, Hekmatirad S, Rahmati M, Velayatipour F, Asghari MH, Saleem A, Moosavi MA. Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166484. [PMID: 35811032 DOI: 10.1016/j.bbadis.2022.166484] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/01/2022] [Accepted: 07/03/2022] [Indexed: 02/08/2023]
Abstract
Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated.
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Affiliation(s)
- Babak Jahangiri
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Patience O Obi
- Applied Health Sciences, University of Manitoba, Winnipeg R3T 2N2, Canada; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg R3T 2N2, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg R3E 3P4, Canada
| | - Narjes Asghari
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Shirin Hekmatirad
- Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Marveh Rahmati
- Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Velayatipour
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Mohammad Hosseni Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Ayesha Saleem
- Applied Health Sciences, University of Manitoba, Winnipeg R3T 2N2, Canada; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg R3T 2N2, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg R3E 3P4, Canada.
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran.
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34
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Camera S, Liscia N, Foti S, Barbieri L, Cossu A, Puccetti F, Elmore U, Rosati R, Scartozzi M, Mazza E, Cascinu S. Does immunotherapy change the treatment paradigm in metastatic gastric cancer? Med Oncol 2022; 39:224. [PMID: 36175723 DOI: 10.1007/s12032-022-01819-4] [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: 06/12/2022] [Accepted: 08/07/2022] [Indexed: 06/16/2023]
Abstract
Gastric cancer represents one of the leading causes of cancer-related death worldwide. Even if the last decade has witnessed an improvement in surgical and systemic treatments, with an increase of overall life expectancy, survival rates still remain unsatisfactory, especially for patients with metastatic disease. Systemic therapies represent the gold standard in the management of stage IV gastric cancer. In this scenario, the availability of effective second and third lines has represented for a long time the only hope to offer an overall survival improvement to these patients. Recently, the advent of immune checkpoint inhibitors has involved also gastric cancer with encouraging efficacy data in the metastatic setting, becoming integral part of the management of selected patients.
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Affiliation(s)
- Silvia Camera
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy.
| | - Nicole Liscia
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Silvia Foti
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Lavinia Barbieri
- Gastrointestinal Surgery Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Andrea Cossu
- Gastrointestinal Surgery Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Francesco Puccetti
- Gastrointestinal Surgery Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Ugo Elmore
- Gastrointestinal Surgery Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Riccardo Rosati
- Gastrointestinal Surgery Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042, Cagliari, Italy
| | - Elena Mazza
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy
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35
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Li Y, Xu C, Wang B, Xu F, Ma F, Qu Y, Jiang D, Li K, Feng J, Tian S, Wu X, Wang Y, Liu Y, Qin Z, Liu Y, Qin J, Song Q, Zhang X, Sujie A, Huang J, Liu T, Shen K, Zhao JY, Hou Y, Ding C. Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals new therapeutic strategies. Nat Commun 2022; 13:5723. [PMID: 36175412 PMCID: PMC9522856 DOI: 10.1038/s41467-022-33282-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 09/12/2022] [Indexed: 11/09/2022] Open
Abstract
Chemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206 tumor tissues from patients with GC undergoing either chemotherapy or anti-HER2-based therapy. Proteome-based classification reveals four subtypes (G-I-G-IV) related to different clinical and molecular features. MSI-sig high GC patients benefit from docetaxel combination treatment, accompanied by anticancer immune response. Further study reveals patients with high T cell receptor signaling respond to anti-HER2-based therapy; while activation of extracellular matrix/PI3K-AKT pathway impair anti-tumor effect of trastuzumab. We observe CTSE functions as a cell intrinsic enhancer of chemosensitivity of docetaxel, whereas TKTL1 functions as an attenuator. Finally, we develop prognostic models with high accuracy to predict therapeutic response, further validated in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemotherapy and targeted therapy in GC.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Bing Wang
- State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan center for outstanding overseas scientists of pulmonary fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, 453007, China
| | - Fujiang Xu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.,Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Fahan Ma
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Yuanyuan Qu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Shanghai, 200032, China.,Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kai Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Jinwen Feng
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Sha Tian
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Xiaohui Wu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Yunzhi Wang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Yang Liu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Zhaoyu Qin
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qi Song
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Xiaolei Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Akesu Sujie
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Kuntang Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Jian-Yuan Zhao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. .,Department of Anatomy and Neuroscience Research Institute, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Chen Ding
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
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36
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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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37
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Third- and Late Line Treatments of Metastatic Gastric Cancer: Still More to Be Done. Curr Oncol 2022; 29:6433-6444. [PMID: 36135075 PMCID: PMC9497544 DOI: 10.3390/curroncol29090506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 12/24/2022] Open
Abstract
In recent years, advances of anticancer and supportive therapies have determined a gradual improvement in survival rates and patients’ general conditions in metastatic gastric cancer (mGC), allowing them to receive further treatments. The choice of treatment is driven by performance status, age, stage of disease, number of metastatic sites and time from the first to third line of treatment. Targets such as microsatellite instability, PD-L1 expression, and HER2 overexpression or amplification may be addressed to personalise treatment and prolong survival. Despite a growing number of third line options that have provided clinicians with greater opportunities to customise treatments, up to date few agents have been demonstrated as effective after two standard lines for mGC; for these reasons, chemotherapy, immunotherapy, and targeted therapy were all widely investigated in both phase II and phase III studies. Overall, TAS-102, apatinib, regorafenib, nilotinib, trastuzumab, and pembrolizumab were demonstrated to be valid options in the third line scenario for mGC patient refractory to at least two lines of therapy. A multimodal approach based on chemotherapy, immunotherapy, targeted agents, a personalised nutritional programme as well as the research of new predictive biomarkers may pave the way to new strategies to identify the best treatment for each patient.
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Drubay V, Nuytens F, Renaud F, Adenis A, Eveno C, Piessen G. Poorly cohesive cells gastric carcinoma including signet-ring cell cancer: Updated review of definition, classification and therapeutic management. World J Gastrointest Oncol 2022; 14:1406-1428. [PMID: 36160745 PMCID: PMC9412924 DOI: 10.4251/wjgo.v14.i8.1406] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/08/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
While the incidence of gastric cancer (GC) in general has decreased worldwide in recent decades, the incidence of diffuse cancer historically comprising poorly cohesive cells-GC (PCC-GC) and including signet ring cell cancer is rising. Literature concerning PCC-GC is scarce and unclear, mostly due to a large variety of historically used definitions and classifications. Compared to other histological subtypes of GC, PCC-GC is nevertheless characterized by a distinct set of epidemiological, histological and clinical features which require a specific diagnostic and therapeutic approach. The aim of this review was to provide an update on the definition, classification and therapeutic strategies of PCC-GC. We focus on the updated histological definition of PCC-GC, along with its implications on future treatment strategies and study design. Also, specific considerations in the diagnostic management are discussed. Finally, the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens (5-Fluorouracil, leucovorin, oxaliplatin and docetaxel), the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.
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Affiliation(s)
- Vincent Drubay
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive Surgery, Cambrai Hospital Center and Sainte Marie, Group of Hospitals of The Catholic Institute of Lille, Cambrai 59400, France
| | - Frederiek Nuytens
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive and Hepatobiliary/Pancreatic Surgery, AZ Groeninge Hospital, Kortrijk 8500, Belgium
| | - Florence Renaud
- Department of Pathology, University Lille Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Antoine Adenis
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
- Department of Medical Oncology, Montpellier Cancer Institute, Monpellier 34000, France
- IRCM, Inserm, University of Monpellier, Monpellier 34000, France
| | - Clarisse Eveno
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
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Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches. Pharmaceutics 2022; 14:pharmaceutics14061303. [PMID: 35745875 PMCID: PMC9227908 DOI: 10.3390/pharmaceutics14061303] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/01/2022] [Accepted: 06/13/2022] [Indexed: 12/03/2022] Open
Abstract
The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer.
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Luo Q, Du R, Liu W, Huang G, Dong Z, Li X. PI3K/Akt/mTOR Signaling Pathway: Role in Esophageal Squamous Cell Carcinoma, Regulatory Mechanisms and Opportunities for Targeted Therapy. Front Oncol 2022; 12:852383. [PMID: 35392233 PMCID: PMC8980269 DOI: 10.3389/fonc.2022.852383] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/03/2022] [Indexed: 12/15/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC), is the most common type of esophageal cancer worldwide, mainly occurring in the Asian esophageal cancer belt, including northern China, Iran, and parts of Africa. Phosphatidlinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important cellular signaling pathways, which plays a crucial role in the regulation of cell growth, differentiation, migration, metabolism and proliferation. In addition, mutations in some molecules of PI3K/Akt/mTOR pathway are closely associated with survival and prognosis in ESCC patients. A large number of studies have found that there are many molecules in ESCC that can regulate the PI3K/Akt/mTOR pathway. Overexpression of these molecules often causes aberrant activation of PI3K/Akt/mTOR pathway. Currently, several effective PI3K/Akt/mTOR pathway inhibitors have been developed, which can play anticancer roles either alone or in combination with other inhibitors. This review mainly introduces the general situation of ESCC, the composition and function of PI3K/Akt/mTOR pathway, and regulatory factors that interact with PI3K/Akt/mTOR signaling pathway. Meanwhile, mutations and inhibitors of PI3K/Akt/mTOR pathway in ESCC are also elucidated.
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Affiliation(s)
- Qian Luo
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Ruijuan Du
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Wenting Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Guojing Huang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Xiang Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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Gong H, Su Y, Zhao L, Ma L, Zhang L, Hou L, Li T, Niu S, Zhang H, Li C, Jin X, Ge L, Leng G, Liu Y. Efficacy and safety of targeted drugs in advanced or metastatic gastric and gastroesophageal junction cancer: A network meta-analysis. J Clin Pharm Ther 2022; 47:493-506. [PMID: 34796971 DOI: 10.1111/jcpt.13570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/25/2021] [Accepted: 11/01/2021] [Indexed: 12/23/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE An increasing number of targeted drugs have been used to treat advanced or metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, the optimal treatment efficacy of these drugs is still controversial. The aims of this study are to systematically summarize the efficacy and safety of current targeted drugs for advanced or metastatic GC and GEJC. METHODS PubMed, EmBase, Cochrane Library, Web of Science and ClinicalTrials were searched for double-blind randomized controlled trials (RCTs) on GC and GEJC up to December 2019. Additionally, we updated the literature search from Jan, 1, 2020 to September 30, 2021. Narrative and quantitative analysis were performed to analyse the efficacy and safety. STATA 15.1 was used to identify publication bias, and the SUCRA (surface under the cumulative ranking) curve was conducted to rank the treatments for each outcome. RESULTS A total of 27 RCTs with 9295 GC and GEJC patients treated by 19 drugs were included. SUCRA showed that regorafenib was the most likely to improve patients' progression-free survival (96.4%), followed by apatinib (90.7%), nivolumab (82.4%), everolimus (76.5%) and pertuzumab (68.5%). Meanwhile, apatinib (92.4%) was most likely to improve overall survival, followed by nivolumab (87.9%), regorafenib (72.5%), olaparib (67.7%) and lapatinib (63.2%). Additionally, neutropenia, diarrhoea and fatigue were the most common adverse events caused by these drugs, followed by pain, nausea, decreased appetite, anaemia and vomiting. WHAT IS NEW AND CONCLUSION Regorafenib and nivolumab have higher efficacy and tolerability and are the most advantageous for advanced GC and GEJC. Moreover, apatinib has higher efficacy but lower tolerability. Everolimus and pertuzumab combined with chemotherapy have best secondary higher efficacy for progression-free survival and good tolerability. Lapatinib and olaparib combined with chemotherapy have moderate efficacy for overall survival and good tolerability.
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Affiliation(s)
- Hongxia Gong
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Yun Su
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Lixia Zhao
- College of Nursing, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Li Ma
- Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
| | - Liying Zhang
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Liangying Hou
- Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
| | - Tingting Li
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Shiwei Niu
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Han Zhang
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Chenghao Li
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
| | - Xiaojie Jin
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Long Ge
- Department of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
| | - Guangxian Leng
- The Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Yongqi Liu
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
- Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, China
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Alsina M, Tabernero J, Diez M. Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond. Cancers (Basel) 2022; 14:1408. [PMID: 35326560 PMCID: PMC8945913 DOI: 10.3390/cancers14061408] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC.
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Affiliation(s)
- Maria Alsina
- Gastrointestinal & Endocrine Tumours Group, Vall d’Hebron Institute of Oncology (VHIO), C/ Natzaret 115-117, 08035 Barcelona, Spain; (M.A.); (M.D.)
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain
| | - Josep Tabernero
- Gastrointestinal & Endocrine Tumours Group, Vall d’Hebron Institute of Oncology (VHIO), C/ Natzaret 115-117, 08035 Barcelona, Spain; (M.A.); (M.D.)
- Medical Oncology Department, Hospital Universitari Vall d’Hebron (HUVH), Universitat Autònoma de Barcelona (UAB), Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain
| | - Marc Diez
- Gastrointestinal & Endocrine Tumours Group, Vall d’Hebron Institute of Oncology (VHIO), C/ Natzaret 115-117, 08035 Barcelona, Spain; (M.A.); (M.D.)
- Medical Oncology Department, Hospital Universitari Vall d’Hebron (HUVH), Universitat Autònoma de Barcelona (UAB), Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Ooki A, Yamaguchi K. The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol 2022; 14:17588359221083049. [PMID: 35281349 PMCID: PMC8908406 DOI: 10.1177/17588359221083049] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. The histology- and morphology-based Lauren classification of GC has been widely used for over 50 years in clinical practice. The Lauren classification divides GC into intestinal and diffuse types, which have distinct etiology, molecular profiles, and clinicopathological features. Diffuse-type GC (DGC) accounts for approximately 30% of GCs. Tumor cells lack adhesion and infiltrate the stroma as single cells or small subgroups, leading to easy dissemination in the abdominal cavity. Clinically, DGC has aggressive traits with a high risk of recurrence and metastasis, which results in unfavorable prognosis. Although systemic chemotherapy is the main therapeutic approach for recurrent or metastatic GC patients, clinical benefits are limited for patients with DGC. Therefore, it is urgent to develop effective therapeutic strategies for DGC patients. Considerable research studies have characterized the molecular and genomic landscape of DGC, of which tight junction protein claudin-18 isoform 2 (CLDN18.2) and fibroblast growing factors receptor-2 isoform IIIb (FGFR2-IIIb) are the most attractive targets because of their close association with DGC. Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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Dong X, Song S, Li Y, Fan Y, Wang L, Wang R, Huo L, Scott A, Xu Y, Pizzi MP, Ma L, Wang Y, Jin J, Zhao W, Yao X, Johnson R, Wang L, Wang Z, Peng G, Ajani JA. Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma-rationale for targeting ARID1A deficiency. Gut 2022; 71:467-478. [PMID: 33785559 PMCID: PMC9724309 DOI: 10.1136/gutjnl-2020-322660] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/20/2021] [Accepted: 03/02/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Gastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A (ARID1A) and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition. METHODS Genomic alterations in ARID1A were analysed in GAC. Mouse gastric epithelial cells from CK19-Cre-Arid1Afl/fl and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC. RESULTS More than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A-/- mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs. CONCLUSIONS The loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.
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Affiliation(s)
- Xiaochuan Dong
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yuan Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, P.R. China
| | - Yibo Fan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Lulu Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Ruiping Wang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Longfei Huo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Ailing Scott
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Yan Xu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, P.R. China
| | - Melissa Pool Pizzi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Lang Ma
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Ying Wang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Jiankang Jin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Wei Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Xiaodan Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Randy Johnson
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Linghua Wang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, P.R. China
| | - Guang Peng
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030;,Corresponding authors: Shumei Song, MD, Ph.D, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; phone: 713-834-6144; fax: 713-745-1163; . Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; phone: 713-792-3685; fax: 713-792-8864;
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Ramírez-Rendon D, Passari AK, Ruiz-Villafán B, Rodríguez-Sanoja R, Sánchez S, Demain AL. Impact of novel microbial secondary metabolites on the pharma industry. Appl Microbiol Biotechnol 2022; 106:1855-1878. [PMID: 35188588 PMCID: PMC8860141 DOI: 10.1007/s00253-022-11821-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/31/2022] [Accepted: 02/05/2022] [Indexed: 12/18/2022]
Abstract
Microorganisms are remarkable producers of a wide diversity of natural products that significantly improve human health and well-being. Currently, these natural products comprise half of all the pharmaceuticals on the market. After the discovery of penicillin by Alexander Fleming 85 years ago, the search for and study of antibiotics began to gain relevance as drugs. Since then, antibiotics have played a valuable role in treating infectious diseases and have saved many human lives. New molecules with anticancer, hypocholesterolemic, and immunosuppressive activity have now been introduced to treat other relevant diseases. Smaller biotechnology companies and academic laboratories generate novel antibiotics and other secondary metabolites that big pharmaceutical companies no longer develop. The purpose of this review is to illustrate some of the recent developments and to show the potential that some modern technologies like metagenomics and genome mining offer for the discovery and development of new molecules, with different functions like therapeutic alternatives needed to overcome current severe problems, such as the SARS-CoV-2 pandemic, antibiotic resistance, and other emerging diseases. KEY POINTS: • Novel alternatives for the treatment of infections caused by bacteria, fungi, and viruses. • Second wave of efforts of microbial origin against SARS-CoV-2 and related variants. • Microbial drugs used in clinical practice as hypocholesterolemic agents, immunosuppressants, and anticancer therapy.
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Affiliation(s)
- Dulce Ramírez-Rendon
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, CDMX, 04510, Mexico City, Mexico
| | - Ajit Kumar Passari
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, CDMX, 04510, Mexico City, Mexico
| | - Beatriz Ruiz-Villafán
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, CDMX, 04510, Mexico City, Mexico
| | - Romina Rodríguez-Sanoja
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, CDMX, 04510, Mexico City, Mexico
| | - Sergio Sánchez
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, CDMX, 04510, Mexico City, Mexico.
| | - Arnold L Demain
- Charles A. Dana Research Institute for Scientists Emeriti (R.I.S.E.), Drew University, Madison, NJ, 07940, USA
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Chen Y, Gong W, Dai W, Jiang H, Xu X. E2F1/2/4 mRNA is associated with immune infiltration and are potential biomarkers for the prognosis of human gastric carcinoma. Transl Cancer Res 2022; 10:2801-2811. [PMID: 35116590 PMCID: PMC8797903 DOI: 10.21037/tcr-21-45] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/27/2021] [Indexed: 12/19/2022]
Abstract
Background E2Fs are genes that regulate DNA synthesis and the cell cycle by encoding a family of transcription factors. Increasing experimental evidence has revealed that E2Fs play key roles in tumor progression in various types of cancer. Methods We investigated the survival, expression and transcriptional data of E2F1/2/4 in gastric cancer (GC) patients using the immunohistochemistry assay, Kaplan-Meier Plotter, cBioPortal, String, and GEPIA databases. The plasma of GC patients was analyzed using the real-time reverse transcription polymerase chain reaction (RT-PCR) assay. The correlation between E2F1/2/4 expression and clinical features was analyzed using the quartile method. As well, the correlation between E2F1/2/4 and GC immune infiltration was also investigated using the TIMER database. Database of Immune Cell Expression (DICE) was also used to analyze correlations between SOX4 and immune responses. Results RT-PCR and tissue immunohistochemistry confirmed that E2F1/2/4 was highly expressed in serum and GC tissue samples of GC patients, the expression of which was not affected by patient age and gender. Also, the survival analysis revealed that low levels of E2F1/2/4 expression were significantly associated with a longer overall survival (OS) in GC patients. E2F1/2/4 was correlated with patient prognosis and immune cell infiltration, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in GC. Our findings indicated that E2F1/2/4 could be used as a prognostic biomarker and indicator of immune infiltration in GC. Conclusions This study revealed that E2F1/2/4 could be a promising indicator for tumor-associated immune infiltration and prognosis in GC patients.
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Affiliation(s)
- Yongyi Chen
- Department of Clinical Lab, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wangang Gong
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Cancer Research Institute, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Wumin Dai
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Cancer Research Institute, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Huifen Jiang
- Department of Clinical Lab, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiaohong Xu
- Department of Clinical Lab, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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Abstract
The prognosis of advanced gastric cancer (AGC) is extremely poor, and the therapeutic effect of traditional palliative chemotherapy is far from satisfactory. To overcome this bottleneck, palliative surgery resection, perioperative chemotherapy combined with surgical resection, hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), radiation therapy, molecular-targeted therapy have been explored in AGC. Although considerable progress has been achieved, there is still no overwhelming therapeutic method. Due to the high heterogeneity of AGC, it is particularly vital to reshaped the paradigm of gastric cancer therapy according to the characteristics of clinical classifications and molecular subtypes.
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Affiliation(s)
- Tao Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yufang He
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Qinglei Zhong
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinhua Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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48
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Targeting lysosomes in human disease: from basic research to clinical applications. Signal Transduct Target Ther 2021; 6:379. [PMID: 34744168 PMCID: PMC8572923 DOI: 10.1038/s41392-021-00778-y] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 09/26/2021] [Indexed: 01/18/2023] Open
Abstract
In recent years, accumulating evidence has elucidated the role of lysosomes in dynamically regulating cellular and organismal homeostasis. Lysosomal changes and dysfunction have been correlated with the development of numerous diseases. In this review, we interpreted the key biological functions of lysosomes in four areas: cellular metabolism, cell proliferation and differentiation, immunity, and cell death. More importantly, we actively sought to determine the characteristic changes and dysfunction of lysosomes in cells affected by these diseases, the causes of these changes and dysfunction, and their significance to the development and treatment of human disease. Furthermore, we outlined currently available targeting strategies: (1) targeting lysosomal acidification; (2) targeting lysosomal cathepsins; (3) targeting lysosomal membrane permeability and integrity; (4) targeting lysosomal calcium signaling; (5) targeting mTOR signaling; and (6) emerging potential targeting strategies. Moreover, we systematically summarized the corresponding drugs and their application in clinical trials. By integrating basic research with clinical findings, we discussed the current opportunities and challenges of targeting lysosomes in human disease.
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Salati M, Venetis K, Fassan M, Malapelle U, Pagni F, Sajjadi E, Fusco N, Ghidini M. ctDNA analysis in the personalized clinical management of gastroesophageal adenocarcinoma: turning hope into reality. Future Oncol 2021; 17:4607-4618. [PMID: 34406032 DOI: 10.2217/fon-2021-0228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/23/2021] [Indexed: 12/14/2022] Open
Abstract
Gastroesophageal adenocarcinoma (GEA) is a global health issue with a high fatality-to-case ratio and a 5-year overall survival that has only slightly improved. High-throughput molecular profiling has uncovered a profound complexity and heterogeneity in GEA biology, which limits considerably the treatment advances. Liquid biopsy with circulating tumor (ct)DNA analysis could elucidate GEA molecular heterogeneity and provide diagnostic, prognostic and predictive information to guide clinical decision-making. However, only a handful of studies have shown positive results for the application of ctDNA analysis in GEA clinical management. As a result, no comprehensive information is available to date on this continuously evolving topic. Here, we discuss the current state of knowledge, along with promises and challenges related to ctDNA analysis in GEA.
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Affiliation(s)
- Massimiliano Salati
- Division of Oncology, Oncology and Hematology Department, University of Modena and Reggio Emilia, Modena, Italy
- Ph.D. Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Konstantinos Venetis
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, Pathology, University Milan Bicocca, Milan 20126, Italy
| | - Elham Sajjadi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Michele Ghidini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
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Kim JH, Zang DY, Jang HJ, Kim HS. A Bayesian network meta-analysis on systemic therapy for previously treated gastric cancer. Crit Rev Oncol Hematol 2021; 167:103505. [PMID: 34656747 DOI: 10.1016/j.critrevonc.2021.103505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 09/14/2021] [Accepted: 10/10/2021] [Indexed: 12/22/2022] Open
Abstract
We conducted a systemic literature review of randomized controlled trials (RCTs) to identify phase III RCTs on salvage treatment of advanced gastric cancer (AGC) and performed a Bayesian network meta-analysis with random-effects model. The overall survival (OS) was the primary outcome of interest. A total of 20 randomized phase III trials were selected. For the second-line treatment, olaparib plus paclitaxel had the highest surface under the cumulative ranking curve value (90.5%), followed by paclitaxel plus ramucirumab (88.4%) and pembrolizumab (86.5%), indicating that these treatments could be the most effective regimens in terms of OS. Nivolumab, chemotherapy, and apatinib showed significant OS benefit compared with best supportive care for the third-line treatment. In conclusion, pembrolizumab may be the most preferable regimen as a second-line treatment for patients with PD-L1-expressing AGC, while paclitaxel-based combinations are recommended for PD-L1-negative AGC. Nivolumab might be the most preferable third-line treatment.
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Affiliation(s)
- Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Dae Young Zang
- Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Republic of Korea
| | - Hyeong Su Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
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