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Basirinia G, Ali M, Comelli A, Sperandeo A, Piana S, Alongi P, Longo C, Di Raimondo D, Tuttolomondo A, Benfante V. Theranostic Approaches for Gastric Cancer: An Overview of In Vitro and In Vivo Investigations. Cancers (Basel) 2024; 16:3323. [PMID: 39409942 PMCID: PMC11476023 DOI: 10.3390/cancers16193323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
Gastric cancer (GC) is the second most common cause of cancer-related death worldwide and a serious public health concern. This high death rate is mostly caused by late-stage diagnoses, which lead to poor treatment outcomes. Radiation immunotherapy and targeted therapies are becoming increasingly popular in GC treatment, in addition to surgery and systemic chemotherapy. In this review, we have focused on both in vitro and in vivo research, which presents a summary of recent developments in targeted therapies for gastric cancer. We explore targeted therapy approaches, including integrin receptors, HER2, Claudin 18, and glutathione-responsive systems. For instance, therapies targeting the integrin receptors such as the αvβ3 and αvβ5 integrins have shown promise in enhancing diagnostic precision and treatment efficacy. Furthermore, nanotechnology provides novel approaches to targeted drug delivery and imaging. These include glutathione-responsive nanoplatforms and cyclic RGD peptide-conjugated nanoparticles. These novel strategies seek to reduce systemic toxicity while increasing specificity and efficacy. To sum up, the review addresses the significance of personalized medicine and advancements in gastric cancer-targeted therapies. It explores potential methods for enhancing gastric cancer prognosis and treatment in the future.
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Affiliation(s)
- Ghazal Basirinia
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy; (D.D.R.); (A.T.)
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy; (G.B.); (M.A.)
| | - Muhammad Ali
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy; (D.D.R.); (A.T.)
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy; (G.B.); (M.A.)
| | - Albert Comelli
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy; (G.B.); (M.A.)
- NBFC—National Biodiversity Future Center, 90133 Palermo, Italy
| | - Alessandro Sperandeo
- Pharmaceutical Factory, La Maddalena S.P.A., Via San Lorenzo Colli, 312/d, 90146 Palermo, Italy; (A.S.); (S.P.)
| | - Sebastiano Piana
- Pharmaceutical Factory, La Maddalena S.P.A., Via San Lorenzo Colli, 312/d, 90146 Palermo, Italy; (A.S.); (S.P.)
| | - Pierpaolo Alongi
- Nuclear Medicine Unit, A.R.N.A.S. Civico Di Cristina e Benfratelli Hospitals, P.zza N. Leotta 4, 90127 Palermo, Italy; (P.A.); (C.L.)
- Advanced Diagnostic Imaging-INNOVA Project, Department of Radiological Sciences, A.R.N.A.S. Civico Di Cristina e Benfratelli Hospitals, P.zza N. Leotta 4, 90127 Palermo, Italy
| | - Costanza Longo
- Nuclear Medicine Unit, A.R.N.A.S. Civico Di Cristina e Benfratelli Hospitals, P.zza N. Leotta 4, 90127 Palermo, Italy; (P.A.); (C.L.)
| | - Domenico Di Raimondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy; (D.D.R.); (A.T.)
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy; (D.D.R.); (A.T.)
| | - Viviana Benfante
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy; (D.D.R.); (A.T.)
- Advanced Diagnostic Imaging-INNOVA Project, Department of Radiological Sciences, A.R.N.A.S. Civico Di Cristina e Benfratelli Hospitals, P.zza N. Leotta 4, 90127 Palermo, Italy
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Dayyani F, Chao J, Lee FC, Taylor TH, Neumann K, Cho MT. A phase II study of cabozantinib and pembrolizumab in advanced gastric/gastroesophageal adenocarcinomas resistant or refractory to immune checkpoint inhibitors. Oncologist 2024; 29:721-e1088. [PMID: 38823034 PMCID: PMC11299925 DOI: 10.1093/oncolo/oyae117] [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: 03/18/2024] [Accepted: 04/19/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. METHODS Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). RESULTS Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed. CONCLUSIONS The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).
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Affiliation(s)
- Farshid Dayyani
- Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Orange, CA 92868, United States
| | - Joseph Chao
- Department of Medical Oncology and Therapeutics Research, City of Hope, CA 91010, United States
| | - Fa-Chyi Lee
- Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Orange, CA 92868, United States
| | - Thomas H Taylor
- Department of Epidemiology and Biostatistics, University of California Irvine, Irvine, CA 92617, United States
| | - Kristen Neumann
- Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Orange, CA 92868, United States
| | - May T Cho
- Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Orange, CA 92868, United States
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Tojjari A, Nagdas S, Saeed A, Saeed A. Deciphering the FGFR2 Code: Innovative Targets in Gastric Cancer Therapy. Curr Oncol 2024; 31:4305-4317. [PMID: 39195304 PMCID: PMC11352315 DOI: 10.3390/curroncol31080321] [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: 06/19/2024] [Revised: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 08/29/2024] Open
Abstract
Gastric cancer (GC) represents a major global health challenge as a highly prevalent disease with high mortality whose global incidence and mortality are predicted to worsen over the coming years. To date, our standard of care for advanced gastric cancer of combination chemotherapy and immunotherapy has a 1-year overall survival rate of 55%. Significant efforts have gone into identifying targetable alterations in gastric cancer, ultimately yielding the Fibroblast Growth Factor Receptors (FGFRs) family, specifically FGFR2 as a promising target. FGFR2 is overexpressed in GC, particularly diffuse-type GC, and is associated with poor prognostic outcomes. In recent years, there has been an increasing number of small molecule inhibitors and monoclonal antibodies targeting FGFR2 that have entered into clinical trials. Specifically for GC, these agents are currently being trialed in various phases as monotherapies or with standard-of-care treatments to make a clinically meaningful impact on what appears to be an important biological axis of GC. In this review, we outline the underlying biology of FGFR2, its putative role in GC, and the various FGFR2-targeted agents currently in clinical trials for gastric cancer patients as well as postulate some challenges in adopting these therapeutics for clinically meaningful benefit.
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Affiliation(s)
- Alireza Tojjari
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15261, USA;
| | | | - Ali Saeed
- Department of Medicine, Ochsner Lafayette General Medical Center, Lafayette, LA 70503, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15261, USA;
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA;
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Zhang X, Zhang X, Geng D, Zhao C, Wang Y, Fan Y, Gao S, Wei J, Zhang F. Targeted therapy for multiple gene mutations in multiple metastases of advanced gastric cancer: a case report. Front Oncol 2023; 13:1257011. [PMID: 38162498 PMCID: PMC10755568 DOI: 10.3389/fonc.2023.1257011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/24/2023] [Indexed: 01/03/2024] Open
Abstract
In China, gastric cancer is the second most common cause of cancer-related death, after lung cancer. At present, the morbidity and mortality rates of gastric cancer are increasing, and targeted therapy for gastric cancer has become a research hotspot. Herein, we report a patient with multiple metastases from advanced gastric cancer. After identifying MET gene amplification, initial treatment induced regression of the tumor. However, in later stages, due to the overexpression or mutation of HER-2, KRAS, TP53, and other genes, the targeted drug therapy became ineffective, and the disease progressed rapidly, leading to the death of the patient.
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Affiliation(s)
- Xin Zhang
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xinran Zhang
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Dandan Geng
- Department of Neurology, The People’s Hospital of Hebei Province, Shijiazhuang, Hebei, China
| | - Chenguang Zhao
- Department of Internal Medicine, Baoding Orthopedic Hospital/People’s Hospital of Lianchi District, Baoding, Hebei, China
| | - Yingnan Wang
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yao Fan
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shasha Gao
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jinmei Wei
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Fengbin Zhang
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Javle M, King G, Spencer K, Borad MJ. Futibatinib, an Irreversible FGFR1-4 Inhibitor for the Treatment of FGFR-Aberrant Tumors. Oncologist 2023; 28:928-943. [PMID: 37390492 PMCID: PMC10628593 DOI: 10.1093/oncolo/oyad149] [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: 03/14/2023] [Accepted: 05/03/2023] [Indexed: 07/02/2023] Open
Abstract
Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors under investigation show reversible binding, and their activity is limited by acquired drug resistance. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor. Futibatinib stands out among FGFR inhibitors because of its covalent binding mechanism and low susceptibility to acquired resistance. Preclinical data indicated robust activity of futibatinib against acquired resistance mutations in the FGFR kinase domain. In early-phase studies, futibatinib showed activity in cholangiocarcinoma, and gastric, urothelial, breast, central nervous system, and head and neck cancers harboring various FGFR aberrations. Exploratory analyses indicated clinical benefit with futibatinib after prior FGFR inhibitor use. In a pivotal phase II trial, futibatinib demonstrated durable objective responses (42% objective response rate) and tolerability in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. A manageable safety profile was observed across studies, and patient quality of life was maintained with futibatinib treatment in patients with cholangiocarcinoma. Hyperphosphatemia, the most common adverse event with futibatinib, was well managed and did not lead to treatment discontinuation. These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches.
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Affiliation(s)
- Milind Javle
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gentry King
- Division of Medical Oncology, University of Washington, Seattle, WA, USA
| | - Kristen Spencer
- Perlmutter Cancer Center of NYU Langone Health, New York, NY, USA
- NYU Grossman School of Medicine, New York University, New York, NY,USA
| | - Mitesh J Borad
- Department of Oncology, Mayo Clinic Cancer Center, Phoenix, AZ,USA
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Gordon A, Johnston E, Lau DK, Starling N. Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments. Onco Targets Ther 2022; 15:1183-1196. [PMID: 36238135 PMCID: PMC9553429 DOI: 10.2147/ott.s282718] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022] Open
Abstract
Despite recent advances in the systemic treatment of gastroesophageal cancers, prognosis remains poor. Comprehensive molecular analyses have characterized the genomic landscape of gastroesophageal cancer that has established therapeutic targets such as human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR) and programmed death ligand 1 (PD-L1). The aberrant fibroblast growth factor receptor 2 (FGFR2) pathway is attractive for targetable therapy with FGFR inhibition based on preclinical data showing a pivotal role in the progression of gastric cancer (GC). FGFR2 amplification is the most common FGFR2 gene aberration in gastroesophageal cancer, and most associated with diffuse GC, which is often linked to poorer prognostic outcomes. There has been considerable progress with drug development focused on FGFR inhibition. At present, there is no approved FGFR inhibitor for FGFR2 positive gastroesophageal cancer. A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC. The role of FGFR signalling, specifically FGFR2, is less established in oesophageal squamous cell cancer (ESCC) with a paucity of evidence for clinical benefit in these patients. Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility. In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.
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Affiliation(s)
- Anderley Gordon
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - Edwina Johnston
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - David K Lau
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK,Correspondence: Naureen Starling, Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom, Tel +44 2086426011, Email
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Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells. Int J Mol Sci 2022; 23:ijms23169108. [PMID: 36012373 PMCID: PMC9409026 DOI: 10.3390/ijms23169108] [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: 06/29/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
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Receptor Tyrosine Kinases Amplified in Diffuse-Type Gastric Carcinoma: Potential Targeted Therapies and Novel Downstream Effectors. Cancers (Basel) 2022; 14:cancers14153750. [PMID: 35954414 PMCID: PMC9367326 DOI: 10.3390/cancers14153750] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 11/28/2022] Open
Abstract
Simple Summary Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric carcinoma with an extremely poor prognosis due to frequent peritoneal metastasis and high probability of recurrence. Its pathogenesis is poorly understood, and consequently, no effective molecular targeted therapy is available. The importance of oncogenic receptor tyrosine kinase (RTK) signaling has been recently demonstrated in the malignant progression of DGC. In particular, RTK gene amplification appears to accelerate peritoneal metastasis. In this review, we provide an overview of RTK gene amplification in DGC and the potential of related targeted therapies. Abstract Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics.
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Harrold E, Corrigan L, Barry S, Lowery M. Targeting MET amplification in Gastro-oesophageal (GO) malignancies and overcoming MET inhibitor resistance: challenges and opportunities. Expert Rev Gastroenterol Hepatol 2022; 16:601-624. [PMID: 35757852 DOI: 10.1080/17474124.2022.2093185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION MET, the hepatocyte growth factor receptor is amplified in 8% of gastroesophageal (GO) malignancies and associated with poor prognosis. Therapeutic targeting of MET amplification and MET mutations has the potential to improve outcomes for patients with GO cancers (GOC). AREAS COVERED The efficacy of MET inhibition (METi) in preclinical studies has yet to translate into meaningful improvements in the treatment paradigm for unselected GOC. MET amplification has been proposed as a superior modality for patient selection; however even if confirmed, frequency and duration of response to METi are limited by rapid activation of primary and secondary resistance pathways. These observations illustrate the challenges inherent in the application of precision oncology predicated on the theory of oncogenic addiction. EXPERT OPINION A standardized definition of MET positivity is critical to enhance patient selection. Early successes targeting the METex14 skipping mutation demonstrate the potent therapeutic effects of METi in a clearly molecularly defined cohort. There is robust preclinical rationale and early-phase data supporting exploitation of immune system interaction with MET. Pragmatic investigation of rational therapeutic combinations based on molecular profiling of both primary and metastatic disease sites with sequential circulating tumor DNA analysis can inform successful clinical development of METi agents in GOC.
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Affiliation(s)
- Emily Harrold
- Medical Oncology Department, Mater Private Hospital Dublin, Leinster, Ireland.,Trinity St James Cancer Institute, Trinity College Dublin, Leinster, Ireland
| | - Lynda Corrigan
- Trinity St James Cancer Institute, Trinity College Dublin, Leinster, Ireland.,Medical Oncology Department, Tallaght/AMNCH Hospital Dublin, Leinster, Ireland
| | - Simon Barry
- Medical Oncology Department, St James University Hospital Dublin, Leinster, Ireland
| | - Maeve Lowery
- Trinity St James Cancer Institute, Trinity College Dublin, Leinster, Ireland.,Medical Oncology Department, St James University Hospital Dublin, Leinster, Ireland
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Nakamura N, Kaida D, Tomita Y, Miyata T, Miyashita T, Fujita H, Kinami S, Ueda N, Takamura H. Intra-tumoral FGFR2 Expression Predicts Prognosis and Chemotherapy Response in Advanced HER2-positive Gastric Cancer Patients. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:293-299. [PMID: 35530644 PMCID: PMC9066533 DOI: 10.21873/cdp.10107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/23/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM This study aimed to evaluate the relationship between clinical outcomes and intra-tumoral fibroblast growth factor receptor 2 (FGFR2) expression in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients who had undergone HER2-targeted chemotherapy. PATIENTS AND METHODS A retrospective analysis was performed in 22 patients with HER2-positive GC, who had undergone systemic chemotherapy. We performed immunohistochemistry staining of FGFR2 expression using surgically resected specimens or biopsied samples and evaluated clinicopathological characteristic and overall survival (OS) in the FGFR2-negative and -positive GC groups. RESULTS A total of 8 and 14 patients were placed in the FGFR2-negative and -positive group, respectively. The median OS rates were 56.2 and 16.0 months in the FGFR2-negative and -positive groups, respectively. The FGFR2-negative group had a significantly better prognosis after HER2-targeted chemotherapy [p=0.027 (log-rank test)]. The univariate analysis revealed that performing gastrectomy, response to combination chemotherapy with trastuzumab, and FGFR2 positivity were significantly correlated with OS. In a multivariate analysis, the response to combination chemotherapy with trastuzumab (p=0.008) was significantly correlated with OS. In addition, the proportions of patients who showed CR or PR in response to chemotherapy were 87.5 and 42.9% in the FGFR2-negative and -positive groups, respectively (p=0.031). CONCLUSION HER2-positive GC patients, without overexpression of FGFR2, exhibited an improved prognosis and response rate to trastuzumab combination chemotherapy. Assessment of intra-tumoral FGFR2 expression could be helpful in predicting the prognosis and response to trastuzumab in HER2-positive GC patients.
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Affiliation(s)
- Naohiko Nakamura
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Daisuke Kaida
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Yasuto Tomita
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Takashi Miyata
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Tomoharu Miyashita
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Hideto Fujita
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Shinichi Kinami
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Nobuhiko Ueda
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
| | - Hiroyuki Takamura
- Department of Surgical Oncology, Kanazawa Medical University Hospital, Ishikawa, Japan
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11
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Shirakihara T, Yamaguchi H, Kondo T, Yashiro M, Sakai R. Transferrin receptor 1 promotes the fibroblast growth factor receptor-mediated oncogenic potential of diffused-type gastric cancer. Oncogene 2022; 41:2587-2596. [PMID: 35338344 DOI: 10.1038/s41388-022-02270-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 03/04/2022] [Indexed: 12/11/2022]
Abstract
Diffuse-type gastric cancer (DGC) is a highly invasive subtype of gastric adenocarcinoma that frequently exhibits scattered peritoneal metastasis. Previous studies have shown that the genes of receptor tyrosine kinases (RTKs), such as fibroblast growth factor receptor 2 (FGFR2) or Met, are amplified in some DGC cell lines, leading to the constitutive activation of corresponding RTKs. In these cell lines, the survival of cancer cells appears to be dependent on the activation of RTKs. To gain novel insights into the downstream signaling pathways of RTKs specific to DGC, phosphotyrosine-containing proteins associated with activated FGFR2 were purified through two sequential rounds of immunoprecipitation from the lysates of two DGC cell lines. As a result, transferrin receptor 1 (TfR1) was identified as the binding partner of FGFR2. Biochemical analysis confirmed that TfR1 protein binds to FGFR2 and is phosphorylated at tyrosine 20 (Tyr20) in an FGFR2 kinase activity-dependent manner. The knockdown of TfR1 and treatment with an inhibitor of FGFR2 caused significant impairment in iron uptake and suppression of cellular proliferation in vitro. Moreover, the suppression of expression levels of TfR1 in the DGC cells significantly reduced their tumorigenicity and potency of peritoneal dissemination. It was indicated that TfR1, when phosphorylated by the binding partner FGFR2 in DGC cells, promotes proliferation and tumorigenicity of these cancer cells. These results suggest that the control of TfR1 function may serve as a therapeutic target in DGC with activated FGFR2.
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Affiliation(s)
- Takuya Shirakihara
- Department of Biochemistry, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hideki Yamaguchi
- Department of Cancer Cell Research, Sasaki Institute, Sasaki Foundation, Tokyo, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Masakazu Yashiro
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ryuichi Sakai
- Department of Biochemistry, Kitasato University School of Medicine, Sagamihara, Japan.
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Zhang X, Wang W, Tian B, Wang Y, Jing J. The Relationship Between D-dimer and Prognosis in the Patients with Serum Alpha-Fetoprotein-Positive Gastric Cancer: A Retrospective Cohort Study. CLINICAL MEDICINE INSIGHTS: ONCOLOGY 2022; 16:11795549221120158. [PMID: 36104997 PMCID: PMC9465609 DOI: 10.1177/11795549221120158] [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: 04/10/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Alpha-fetoprotein-positive gastric cancer (AFPGC) is a subtype of gastric
cancer that is rare in clinical practice and extremely malignant. Malignant
tumors are often associated with hemorrhage, thrombosis, and even
disseminated intravascular coagulation (DIC). The D-dimer test is used as a
sensitive index in the diagnosis of DIC and fresh thrombosis in malignant
tumors. Therefore, this study aims to investigate the relationship between
D-dimer values and the clinical characteristics and prognosis of patients
with serum AFPGC (AFP ⩾ 15 μg/L) patients. Methods: Overall, 120 healthy subjects and 120 AFP-negative gastric cancer (AFP <
15μg/L) patients from May 2017 to July 2018 at the Shanxi Cancer Hospital
served as the control group in this retrospective cohort study.
Additionally, 120 patients with pretreatment advanced serum AFP were chosen
to analyze clinicopathologic features and factors that affect prognosis. The
predictor was the D-dimer, and the outcome variable was overall survival
(OS). Other variables included age, sex, tumor site, T-stage, distant
metastasis, and preoperative serum tumor biomarkers. Differences in OS rate
were analyzed by GraphPad Prism 9.2.0.332. The Cox regression model was used
for univariate and multivariate analysis. Results: In comparison to AFP-negative gastric cancer, we discovered that D-dimer had
a meaningfully higher presentation in patients with AFPGC
(P < .001). Based on D-dimer median levels, the
AFPGC patients were divided into two groups, including 39 patients with low
D-dimer (<1000 ng/mL) and 81 patients with high D-dimer (⩾1000 ng/mL).
The variables, including T-stage, distant metastasis, and expression of
HER2, were associated with the value of D-dimer. The
D-dimer levels were weakly related to the levels of tumor markers. The
differences in AFPGC patients, with an OS rate of 30.76% for patients with
low D-dimer (<1000) and 12.30% with high D-dimer (⩾1000;
P = .0027), were statistically significant. Cox
multivariate analysis of various parameters indicated that T-stage, distant
metastasis, vascular embolism, level of D-dimer, and tumor biomarkers of AFP
were independent risk factors for survival. Conclusion: Serum D-dimer levels may be a valuable indicator for predicting AFPGC
metastasis and progression.
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Affiliation(s)
- Xiaofang Zhang
- Department of Etiology and tumor marker
laboratory, Shanxi Province Cancer Hospital, Taiyuan, China
- Shanxi Hospital Affiliated to Cancer
Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
- Cancer Hospital Affiliated to Shanxi
Medical University, Taiyuan, China
| | - Weigang Wang
- Department of Etiology and tumor marker
laboratory, Shanxi Province Cancer Hospital, Taiyuan, China
- Shanxi Hospital Affiliated to Cancer
Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
- Cancer Hospital Affiliated to Shanxi
Medical University, Taiyuan, China
| | - Baoguo Tian
- Department of Etiology and tumor marker
laboratory, Shanxi Province Cancer Hospital, Taiyuan, China
- Shanxi Hospital Affiliated to Cancer
Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
- Cancer Hospital Affiliated to Shanxi
Medical University, Taiyuan, China
| | - Yan Wang
- Department of Etiology and tumor marker
laboratory, Shanxi Province Cancer Hospital, Taiyuan, China
- Shanxi Hospital Affiliated to Cancer
Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
- Cancer Hospital Affiliated to Shanxi
Medical University, Taiyuan, China
| | - Jiexian Jing
- Department of Etiology and tumor marker
laboratory, Shanxi Province Cancer Hospital, Taiyuan, China
- Shanxi Hospital Affiliated to Cancer
Hospital, Chinese Academy of Medical Sciences, Taiyuan, China
- Cancer Hospital Affiliated to Shanxi
Medical University, Taiyuan, China
- Jiexian Jing, Department of Etiology and
tumor marker laboratory, Shanxi Province Cancer Hospital, Shanxi Province,
030013 Taiyuan, China.
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13
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Ooki A, Yamaguchi K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer 2021; 24:1169-1183. [PMID: 34398359 DOI: 10.1007/s10120-021-01235-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
Despite recent advances in the systemic treatment of metastatic gastric cancer (GC), prognostic outcomes remain poor. Considerable research effort has been invested in characterizing the genomic landscape of GC and identifying potential therapeutic targets. FGFR2 is one of the most attractive targets because aberrations in this gene are frequently associated with GC, particularly the diffuse type in Lauren's classification, which confers an unfavorable prognosis. Based on the preclinical data, the FGFR2 signaling pathway plays a key role in the development and progression of GC, and several FGFR inhibitors have been clinically assessed. However, the lack of robust treatment efficacy has hampered precision medicine for patients with FGFR2-aberrant GC. Recently, the clinical benefits of the FGFR2-IIIb-selective monoclonal antibody bemarituzumab for FGFR2b-positive GC patients were shown in a randomized phase II FIGHT trial of bemarituzumab combined with the first-line chemotherapy. This trial demonstrates proof of concept, suggesting that FGFR2 is a relevant therapeutic target for patients with FGFR2b-positive GC and that bemarituzumab brings new hope for diffuse-type GC patients. In this review, we summarize the oncogenic roles of FGFR2 signaling and highlight the most recent advances in FGFR inhibitors based on the findings of pivotal clinical trials for patients with FGFR2-aberrant GC. Thus, the era of precision medicine for patients with FGFR2-aberrant GC will be opened.
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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, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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14
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Liu M. Combination treatment with trastuzumab and crizotinib in metastatic gastric cancer harboring Her-2 amplification and c-MET amplification: A case report. Medicine (Baltimore) 2021; 100:e27017. [PMID: 34516491 PMCID: PMC8428754 DOI: 10.1097/md.0000000000027017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/05/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Metastatic gastric cancer patients with poor eastern cooperative oncology group performance status (PS) (≥3) were lack of effective anti-tumor strategies. They always lived with poor PS, severe and multiple symptoms, and usually resulted in extremely limited survival time. Herein, we reported a patient diagnosed with gastric cancer metastasized to multiple bones, along with lymphangitis carcinomatosa in lungs, harboring Her-2 and c-MET amplification with poor PS, positively responded to combinational therapy with trastuzumab and crizotinib. PATIENT CONCERNS The patient complained of persistent cough and fatigue for 2 months, otherwise, she denied smoking, alcohol history, or any other medical or family history. DIAGNOSIS With the biopsy results from gastroscopy, as well as computer tomography for chest and abdomen, the patient was diagnosed as gastric adenocarcinoma, with metastasis on lungs, left adrenal gland, retroperitoneal lymph nodes, and multiple bones. INTERVENTIONS Because of the poor PS (PS = 3), as well as Her-2 and c-MET amplification, the patient received combination treatment with trastuzumab and crizotinib as salvage strategy. OUTCOMES After 2 months' exposure of trastuzumab and crizotinib, symptoms including persistent cough, and chest distress were alleviated significantly. Simultaneously, chest computer tomography showed significant dissipation of lymphangitis carcinomatosa, as well as apparent reduction of pleural effusion. No adverse reactions including nausea, vomiting, diarrhea, or hypertension was observed during the following 2 months. LESSONS The present case suggested that combinational therapy with trastuzumab and crizotinib might be effective in metastatic gastric cancer patients harboring Her-2 and c-MET amplification, even with a poor PS. It was also implied that gene sequencing might be valuable, especially in patients with limited treatment strategies.
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15
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Fong CYK, Chau I. Harnessing biomarkers of response to improve therapy selection in esophago-gastric adenocarcinoma. Pharmacogenomics 2021; 22:703-726. [PMID: 34120461 PMCID: PMC8265282 DOI: 10.2217/pgs-2020-0090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 04/21/2021] [Indexed: 12/16/2022] Open
Abstract
Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.
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Affiliation(s)
- Caroline YK Fong
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK
| | - Ian Chau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK
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16
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Kim S, Ahn JM, Bae WJ, Han JH, Lee D. Quantitation of ligand is critical for ligand-dependent MET signalling activation and determines MET-targeted therapeutic response in gastric cancer. Gastric Cancer 2021; 24:577-588. [PMID: 33164142 DOI: 10.1007/s10120-020-01139-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite the promising preclinical antitumor activity of MET-targeting therapies, most clinical trials have failed. We introduced a new concept of quantitation of stroma-induced hepatocyte growth factor (HGF) to assess the actual MET signalling activity in gastric cancer (GC). METHODS We treated serially diluted HGF and conditioned media (CM) from cancer-associated fibroblasts (CAFs) on low MET-expressing cancer cells and investigated the phenotypical and signalling changes. Stromal proportion and MET expression in GC samples were assessed, and gene set enrichment analysis (GSEA) from the public database was performed. The antitumor effect of anti-MET treatment was examined, especially when cancer cells were activated in a ligand-dependent manner. RESULTS Relatively high doses of HGF or high-concentrated CM fully activated MET signalling cascades and promoted cell proliferation/invasion. High stromal proportion denoted worse patient survival in MET-positive GCs than in MET-negative ones. GSEA showed that the gene sets regarding proliferation, migration, and CAF as well as MET pathway signature were enriched in simultaneously MET- and HGF-positive samples. Sufficient ligand-dependent MET signalling activation increased the sensitivity to crizotinib. CONCLUSIONS We conclude that patients whose tumours have a high stromal proportion and at least low MET expression may benefit more from MET-targeted therapies.
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Affiliation(s)
- Seokhwi Kim
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Ji Mi Ahn
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Won Jung Bae
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Jae Ho Han
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Dakeun Lee
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea.
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Clinical difference between fibroblast growth factor receptor 2 subclass, type IIIb and type IIIc, in gastric cancer. Sci Rep 2021; 11:4698. [PMID: 33633310 PMCID: PMC7907198 DOI: 10.1038/s41598-021-84107-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Fibroblast growth factor receptor 2 (FGFR2) has two isoforms: IIIb type and IIIc type. Clinicopathologic significance of these two FGFR2 subtypes in gastric cancer remains to be known. This study aimed to clarify the clinicopathologic difference of FGFR2IIIb and/or FGFR2IIIc overexpression. A total of 562 patients who underwent gastrectomy was enrolled. The expressions of FGFR2IIIb and FGFR2IIIc were retrospectively examined by immunohistochemistry or fluorescence in situ hybridization (FISH) using the 562 gastric tumors. We evaluated the correlation between clinicopathologic features and FGFR2IIIb overexpression and/or FGFR2IIIc overexpression in gastric cancer. FGFR2IIIb overexpression was observed in 28 cases (4.9%), and FGFR2IIIc overexpression was observed in four cases (0.7%). All four FGFR2IIIc cases were also positive for FGFR2IIIb, but not in the same cancer cells. FGFR2IIIb and/or FGFR2IIIc overexpression was significantly correlated with lymph node metastasis and clinical stage. Both FGFR2IIIb and FGFR2IIIc were significantly associated with poor overall survival. A multivariate analysis showed that FGFR2IIIc expression was significantly correlated with overall survival. FISH analysis indicated that FGFR2 amplification was correlated with FGFR2IIIb and/or FGFR2IIIc overexpression. These findings suggested that gastric tumor overexpressed FGFR2IIIc and/or FGFR2IIIb at the frequency of 4.9%. FGFR2IIIc overexpression might be independent prognostic factor for patients with gastric cancer.
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18
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Wallander K, Eisfeldt J, Lindblad M, Nilsson D, Billiau K, Foroughi H, Nordenskjöld M, Liedén A, Tham E. Cell-free tumour DNA analysis detects copy number alterations in gastro-oesophageal cancer patients. PLoS One 2021; 16:e0245488. [PMID: 33539436 PMCID: PMC7861431 DOI: 10.1371/journal.pone.0245488] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 12/30/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Analysis of cell-free tumour DNA, a liquid biopsy, is a promising biomarker for cancer. We have performed a proof-of principle study to test the applicability in the clinical setting, analysing copy number alterations (CNAs) in plasma and tumour tissue from 44 patients with gastro-oesophageal cancer. METHODS DNA was isolated from blood plasma and a tissue sample from each patient. Array-CGH was applied to the tissue DNA. The cell-free plasma DNA was sequenced by low-coverage whole-genome sequencing using a clinical pipeline for non-invasive prenatal testing. WISECONDOR and ichorCNA, two bioinformatic tools, were used to process the output data and were compared to each other. RESULTS Cancer-associated CNAs could be seen in 59% (26/44) of the tissue biopsies. In the plasma samples, a targeted approach analysing 61 regions of special interest in gastro-oesophageal cancer detected cancer-associated CNAs with a z-score >5 in 11 patients. Broadening the analysis to a whole-genome view, 17/44 patients (39%) had cancer-associated CNAs using WISECONDOR and 13 (30%) using ichorCNA. Of the 26 patients with tissue-verified cancer-associated CNAs, 14 (54%) had corresponding CNAs in plasma. Potentially clinically actionable amplifications overlapping the genes VEGFA, EGFR and FGFR2 were detected in the plasma from three patients. CONCLUSIONS We conclude that low-coverage whole-genome sequencing without prior knowledge of the tumour alterations could become a useful tool for cell-free tumour DNA analysis of total CNAs in plasma from patients with gastro-oesophageal cancer.
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Affiliation(s)
- Karin Wallander
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Jesper Eisfeldt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Mats Lindblad
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Kenny Billiau
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Hassan Foroughi
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Nordenskjöld
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Agne Liedén
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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19
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[Intratumoral heterogeneity of gastric cancer-impact on biomarker evaluation]. DER PATHOLOGE 2021; 41:76-82. [PMID: 33427920 DOI: 10.1007/s00292-020-00881-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/23/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Gastric carcinomas often measure more than 5 cm at primary diagnosis. Predictive biomarker testing is usually carried out on tissue biopsies, which do not represent the entire tumor biology and intratumoral heterogeneity. OBJECTIVES The aim of this study was to explore gastric cancer's intratumoral heterogeneity and its impact on the evaluation of predictive and prognostic biomarkers. MATERIALS AND METHODS The study cohort consisted of approximately 500 patients with therapy-naive adenocarcinomas of the stomach or the esophagogastric junction. The following biomarkers were determined: HER2, MET, Ki67, PD-L1/PD‑1, VISTA, EBV-status, and PIK3CA. RESULTS All examined biomarkers were influenced by gastric cancer's intratumoral heterogeneity. Tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate tumor classification in a clinical setting. CONCLUSIONS Our findings unravel issues of tumor heterogeneity in gastric cancer. Biomarker diagnostics on tissue biopsies should be carried out on at least five biopsies of different tumor areas. If possible, biomarker diagnostics should be repeated on resection specimens. Tissue microarrays should no longer be used for research studies of gastric cancer.
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20
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SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells. Int J Mol Sci 2020; 22:ijms22010082. [PMID: 33374770 PMCID: PMC7796274 DOI: 10.3390/ijms22010082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/12/2022] Open
Abstract
MET-amplified gastric cancer cells are extremely sensitive to MET inhibition in vitro, whereas clinical efficacy of MET inhibitors is disappointing. The compensatory activation of other oncogenic growth factor receptors may serve as an underlying mechanism of resistance. In this study, we analyzed the role of HER receptors, in particular HER3 and its ligand heregulin, in this respect. This also included the chromatin-organizer protein SATB1, as an established regulator of HER expression in other tumor entities. In a panel of MET-amplified gastric carcinoma cell lines, cell growth under anchorage-dependent and independent conditions was studied upon inhibitor treatment or siRNA-mediated knockdown. Expression analyses were performed using RT-qPCR, FACS, and immunoblots. Signal transduction was monitored via antibody arrays and immunoblots. As expected, MET inhibition led to a growth arrest and inhibition of MAPK signaling. Strikingly, however, this was accompanied by a rapid and profound upregulation of the oncogenic receptor HER3. This finding was determined as functionally relevant, since HER3 activation by HRG led to partial MET inhibitor resistance, and MAPK/Akt signaling was even found enhanced upon HRG+MET inhibitor treatment compared to HRG alone. SATB1 was identified as mediator of HER3 upregulation. Concomitantly, SATB1 knockdown prevented upregulation of HER3, thus abrogating the HRG-promoted rescue from MET inhibition. Taken together, our results introduce the combined HER3/MET inhibition as strategy to overcome resistance towards MET inhibitors.
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21
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El Darsa H, El Sayed R, Abdel-Rahman O. MET Inhibitors for the Treatment of Gastric Cancer: What's Their Potential? J Exp Pharmacol 2020; 12:349-361. [PMID: 33116950 PMCID: PMC7547764 DOI: 10.2147/jep.s242958] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.
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Affiliation(s)
- Haidar El Darsa
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rola El Sayed
- Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar Abdel-Rahman
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
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22
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Zhao C, Feng Z, He H, Zang D, Du H, Huang H, Du Y, He J, Zhou Y, Nie Y. Protein expression-based classification of gastric cancer by immunohistochemistry of tissue microarray. PLoS One 2020; 15:e0238836. [PMID: 33095797 PMCID: PMC7584200 DOI: 10.1371/journal.pone.0238836] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 08/25/2020] [Indexed: 12/21/2022] Open
Abstract
Recently, the Cancer Genome Atlas and Asian Cancer Research Group propose two new classifications system of gastric cancer by using multi-platforms of molecular analyses. However, these highly complicated and cost technologies have not yet been translated into full clinical utility. In addition, the clinicians are expected to gain more guidance of treatment for different molecular subtypes. In this study, we developed a panel of gastric cancer patients in population from Southern China using commercially accessible TMA and immunohistochemical technology. A cohort of 259 GC patients was classified into 4 subtypes on the basis of expression of mismatch repair proteins (PMS2, MLH1, MSH2, and MSH6), E-cadherin and p21 protein. We observed that the subtypes presented distinct prognosis. dMMR-like subtype was associated with the best prognosis, and E-cadherin-a subtype was associated with the worst prognosis. Patients with p21-High and p21-Ligh subtypes had intermediate overall survival. In multivariate analysis, the dMMR-like subtype remained an independent prediction power for overall survival in the model. We described a molecular classification of gastric cancers using clinically applicable assay. The biological relevance of the four subtypes was illustrated by significant differences in prognosis. Our molecular classification provided an effective and inexpensive screening tool for improving prognostic models. Nevertheless, our study should be considered preliminary and carries a limited predictive value as a single-center retrospective study.
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Affiliation(s)
- Chong Zhao
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhiqiang Feng
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Hongzhen He
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Dan Zang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Hong Du
- Department of Pathology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
| | - Hongli Huang
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yanlei Du
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jie He
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yongjian Zhou
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
- * E-mail: (YN); (YZ)
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
- * E-mail: (YN); (YZ)
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23
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Oberlick EM, Rees MG, Seashore-Ludlow B, Vazquez F, Nelson GM, Dharia NV, Weir BA, Tsherniak A, Ghandi M, Krill-Burger JM, Meyers RM, Wang X, Montgomery P, Root DE, Bieber JM, Radko S, Cheah JH, Hon CSY, Shamji AF, Clemons PA, Park PJ, Dyer MA, Golub TR, Stegmaier K, Hahn WC, Stewart EA, Schreiber SL, Roberts CWM. Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors. Cell Rep 2020; 28:2331-2344.e8. [PMID: 31461650 DOI: 10.1016/j.celrep.2019.07.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 04/19/2019] [Accepted: 07/08/2019] [Indexed: 02/09/2023] Open
Abstract
Cancer is often seen as a disease of mutations and chromosomal abnormalities. However, some cancers, including pediatric rhabdoid tumors (RTs), lack recurrent alterations targetable by current drugs and need alternative, informed therapeutic options. To nominate potential targets, we performed a high-throughput small-molecule screen complemented by a genome-scale CRISPR-Cas9 gene-knockout screen in a large number of RT and control cell lines. These approaches converged to reveal several receptor tyrosine kinases (RTKs) as therapeutic targets, with RTK inhibition effective in suppressing RT cell growth in vitro and against a xenograft model in vivo. RT cell lines highly express and activate (phosphorylate) different RTKs, creating dependency without mutation or amplification. Downstream of RTK signaling, we identified PTPN11, encoding the pro-growth signaling protein SHP2, as a shared dependency across all RT cell lines. This study demonstrates that large-scale perturbational screening can uncover vulnerabilities in cancers with "quiet" genomes.
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Affiliation(s)
- Elaine M Oberlick
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA
| | | | - Brinton Seashore-Ludlow
- Broad Institute, Cambridge, MA 02142, USA; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden
| | | | - Geoffrey M Nelson
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA
| | - Neekesh V Dharia
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Boston Children's Hospital, Boston, MA 02115, USA
| | | | | | | | | | | | - Xiaofeng Wang
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | | | | | - Sandi Radko
- Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | | | | | | | | | - Peter J Park
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Dyer
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Todd R Golub
- Broad Institute, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kimberly Stegmaier
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Boston Children's Hospital, Boston, MA 02115, USA
| | - William C Hahn
- Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Elizabeth A Stewart
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Stuart L Schreiber
- Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
| | - Charles W M Roberts
- Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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24
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Zhu C, Shi H, Wu M, Wei X. A dual MET/AXL small-molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment. MedComm (Beijing) 2020; 1:103-118. [PMID: 34766112 PMCID: PMC8489669 DOI: 10.1002/mco2.11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 02/05/2023] Open
Abstract
The receptor tyrosine kinases MET and AXL have been implicated in tumorigenesis and aggressiveness of multiple malignancies. We performed this study to evaluate the antitumor impact of LY2801653, a dual MET and AXL inhibitor on gastric cancer and to elucidate the underlying mechanisms. In the present study, tissue microarrays containing gastric cancer tissues were stained with MET and AXL antibodies, which showed the prognostic values of MET and AXL. Administration of LY2801653 inhibited cell proliferation, migration, epithelial‐mesenchymal transition, induced apoptosis, and cell cycle arrest. Xenograft mouse models showed suppressed cell proliferation of tumors in high MET and AXL expression cells. LY2801653 also inhibited the growth of MET and AXL‐independent cells at higher but clinically relevant doses through decreased angiogenesis and M2 macrophages in the tumor microenvironment. In conclusion, our study provides evidence for MET and AXL as prognostic biomarkers and potential therapeutic targets in gastric cancer. The dual MET/AXL inhibitor LY2801653 represents a promising therapeutic strategy for the treatment of patients with gastric carcinoma.
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Affiliation(s)
- Chenjing Zhu
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China.,Department of Radiation Oncology Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University Nanjing Jiangsu China
| | - Huashan Shi
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
| | - Min Wu
- Department of Biomedical Sciences School of Medicine and Health Sciences University of North Dakota Grand Forks North Dakota USA
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
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25
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Mitra S, Bal A, Kashyap D, Kumar S, Shrivastav S, Das A, Singh G. Tumour angiogenesis and c-Met pathway activation - implications in breast cancer. APMIS 2020; 128:316-325. [PMID: 31991499 DOI: 10.1111/apm.13031] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/23/2020] [Indexed: 11/29/2022]
Abstract
Breast cancer is a heterogeneous disease with wide range of clinical behaviour. Tumour angiogenesis and metastasis have been considered as prognostic markers of the breast carcinoma, and c-Met, a transmembrane receptor tyrosine kinase has been implicated in both these processes of tumour progression. This study was conducted to elucidate c-Met and downstream signalling pathways in breast cancer and correlate with angiogenesis as assessed by microvessel density (MVD) and other prognostic parameters including lymph node metastases. Microvessel density (MVD) was assessed by endothelial cell (CD34) marker in breast cancers. c-Met was evaluated by immunohistochemistry for protein expression and by copy number assay for amplification at gene level. PCR array for gene expression related to c-Met, RAS-MAPK, PI3K-AKT and angiogenesis pathway was performed by real-time PCR. c-Met protein, copy number and mRNA expression did not differ significantly with the lymph node status or MVD. However, Her-2 overexpressing group showed c-Met protein overexpression and amplification. c-Met protein overexpression was also noted in the Luminal B subtype though no amplification was noted. Thus, the c-Met immunohistochemistry score and the c-MET copy numbers did not correlate with each other. c-Met downstream pathway genes (RAS-MAPK, PI3K-AKT and angiogenesis pathway) showed significant upregulation in Luminal B molecular subtype, lymph node-positive cases and cases with high MVD. The downstream signalling pathways (angiogenesis, RAS-MAPK and PI3K-AKT) were associated high MVD, lymph node metastases, and Her-2 and Luminal B subtype. Since inhibitors of these pathways are commercially available, these can be of therapeutic significance.
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Affiliation(s)
| | - Amanjit Bal
- Department of Histopathology, PGIMER, Chandigarh, India
| | | | - Sandeep Kumar
- Department of Histopathology, PGIMER, Chandigarh, India
| | | | - Ashim Das
- Department of Histopathology, PGIMER, Chandigarh, India
| | - Gurpreet Singh
- Department of General Surgery, PGIMER, Chandigarh, India
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26
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Moosavi F, Giovannetti E, Saso L, Firuzi O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit Rev Clin Lab Sci 2019; 56:533-566. [PMID: 31512514 DOI: 10.1080/10408363.2019.1653821] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 07/13/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022]
Abstract
Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.
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Affiliation(s)
- Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc) , Amsterdam , The Netherlands
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza Onlus , Pisa , Italy
| | - Luciano Saso
- Department of Physiology and Pharmacology, "Vittorio Erspamer," Sapienza University , Rome , Italy
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
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27
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Fernández-Nogueira P, Mancino M, Fuster G, López-Plana A, Jauregui P, Almendro V, Enreig E, Menéndez S, Rojo F, Noguera-Castells A, Bill A, Gaither LA, Serrano L, Recalde-Percaz L, Moragas N, Alonso R, Ametller E, Rovira A, Lluch A, Albanell J, Gascon P, Bragado P. Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation. Clin Cancer Res 2019; 26:1432-1448. [DOI: 10.1158/1078-0432.ccr-19-0353] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 09/15/2019] [Accepted: 11/04/2019] [Indexed: 11/16/2022]
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28
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Evaluation of Intratumoral and Intertumoral Heterogeneity of MET Protein Expression in Gastric Cancer. Appl Immunohistochem Mol Morphol 2019; 26:445-453. [PMID: 28968267 DOI: 10.1097/pai.0000000000000448] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tumor heterogeneity of a target molecule could contribute to failure of the targeted therapy. We investigated the heterogeneity of MET expression within same primary gastric cancer (GC) and between primary and corresponding secondary GC lesions using immunohistochemistry (IHC). Intratumoral heterogeneity was defined as discordant MET status among 3 tissue microarray cores (3 different areas of same tumor). IHC 3+ was considered positive for MET overexpression. MET overexpression was observed in 2.7% (50/1869) of all examined cores and 5.3% (33/623) of primary GCs. When we compared MET IHC results between 3 cores from each tumor, intratumoral heterogeneity was identified (65.0% in total 623 cases; 84.4% in 480 cases with any staining intensity; 84.9% in 251 cases with moderate to strong intensity; 90.9% in 33 cases with strong intensity). Of 33 MET-overexpressed GCs, the average proportion of strongly stained area was 19.6% in the whole sections. Of 269 cases with primary GC and regional lymph node metastasis, 17 (6.3%) showed MET positivity in which 9 (52.9%) were discordant (negative conversion). In 123 cases with primary and corresponding local recurrent/distant metastatic GC, 3 (2.4%) showed MET positivity in which 2 (66.7%) were discordant (positive conversion). In the survival analysis, MET IHC 3+ in lymph node metastases was an independent negative prognostic factor for overall survival. We found that MET overexpression is uncommon and highly heterogeneous in GC. This severe heterogeneity of MET status should be considered in tissue sampling and development of biomarkers for anti-MET therapy.
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29
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Shen B, Wu F, Ye J, Liang R, Wang R, Yu R, Wu X, Shao YW, Feng J. Crizotinib-resistant MET mutations in gastric cancer patients are sensitive to type II tyrosine kinase inhibitors. Future Oncol 2019; 15:2585-2593. [PMID: 31339066 DOI: 10.2217/fon-2019-0140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim: Crizotinib has been used to counter MET amplification in different human malignancies. However, transient responses were observed in some patients with rapid acquisition of resistant mutations in MET. Materials & methods: MET mutations stably expressed Ba/F3 cell lines were used for IC50 detection. Signaling pathway analysis was done using 293T cell line. Results: Four MET mutations conferred resistance to crizotinib with sustained activation of downstream signaling pathways of MET. On the other hand, the four MET mutations displayed different response to type II tyrosine kinase inhibitors with variable deterioration of the downstream signals. Conclusion: This study suggested that patients carrying MET V1092L, D1228G or Y1230H mutations could benefit from type II tyrosine kinase inhibitor treatment, but not patients with G1163R or D1228Y/N mutations.
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Affiliation(s)
- Bo Shen
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu, 210009, PR China
| | - Feixiang Wu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, PR China.,Guangxi Liver Cancer Diagnosis & Treatment Engineering & Technology Research Center, PR China.,Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor, Ministry of Education, PR China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, PR China
| | - Rong Liang
- Department of Digestive Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, PR China
| | - Ruping Wang
- Department of Research & Development, Nanjing Geneseeq Technology, Inc., Nanjing, Jiangsu, PR China
| | - Ruoying Yu
- Translational Medicine Research Institute, Geneseeq Technology, Inc., Toronto, Ontario, M5G1L7, Canada
| | - Xue Wu
- Translational Medicine Research Institute, Geneseeq Technology, Inc., Toronto, Ontario, M5G1L7, Canada
| | - Yang W Shao
- Translational Medicine Research Institute, Geneseeq Technology, Inc., Toronto, Ontario, M5G1L7, Canada
| | - Jifeng Feng
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu, 210009, PR China
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30
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Kim ST, Lee IK, Rom E, Sirkis R, Park SH, Park JO, Park YS, Lim HY, Kang WK, Kim KM, Yayon A, Lee J. Neutralizing antibody to FGFR2 can act as a selective biomarker and potential therapeutic agent for gastric cancer with FGFR2 amplification. Am J Transl Res 2019; 11:4508-4515. [PMID: 31396354 PMCID: PMC6684926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 05/30/2019] [Indexed: 06/10/2023]
Abstract
Fibroblast growth factor receptor 2 (FGFR2) amplification has been reported in 5-10% of gastric cancer (GC) and is associated with poor prognosis. In this study, we characterized the anti-tumor effect of PRO-007, a newly developed recombinant monoclonal antibody that targets FGFR2, in GC cell lines KATO III (with FGFR2 amplification) and NCI-N87 (without FGFR2 amplification). Validation was performed in parallel using two patient-derived tumor cells (PDCs) from patients with GC. Cell viability assays were performed using FGFR2-transfected NCI-N87 cells and FGFR2-knockdown KATO III cells that were generated using short hairpin RNA (shRNA). PRO-007 reduced KATO III cell viability (P = 0.0034) but not that of NCI-N87 cells (P = 0.3710). PRO-007 also significantly reduced KATO III cell invasiveness (P < 0.0001) but not NCI-N87 cell invasiveness (P = 0.8136). Immunoblot analysis showed that PRO-007 treatment decreased the levels of phosphorylated AKT and ERK. The FGFR2-inhibitory activity of PRO-007 was confirmed in genetically modified GC cell lines. Cell viability of FGFR2-overexpressing NCI-N87 cells was significantly decreased by PRO-007, while KATO III cells were significantly resistant to the treatment when FGFR2 was knocked down by FGFR2 shRNA transfection. Furthermore, PRO-007 had a synergistic effect with ramucirumab on the invasiveness of cancer cells with FGFR2 amplification. Consistent results were obtained using PDCs from patients with GC. Overall, these preclinical data support the further clinical development of PRO-007 as a potential therapeutic agent for patients with FGFR2-amplified GC.
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - In Kyoung Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Eran Rom
- Fibron Ltd., Weizmann Science ParkNess Ziona, Israel
| | - Roy Sirkis
- Fibron Ltd., Weizmann Science ParkNess Ziona, Israel
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
| | - Avner Yayon
- Fibron Ltd., Weizmann Science ParkNess Ziona, Israel
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, Korea
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31
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Zhang J, Tang PMK, Zhou Y, Cheng ASL, Yu J, Kang W, To KF. Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis. Cells 2019; 8:cells8060637. [PMID: 31242658 PMCID: PMC6627225 DOI: 10.3390/cells8060637] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/14/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most wide-spread malignancies in the world. The oncogenic role of signaling of fibroblast growing factors (FGFs) and their receptors (FGFRs) in gastric tumorigenesis has been gradually elucidated by recent studies. The expression pattern and clinical correlations of FGF and FGFR family members have been comprehensively delineated. Among them, FGF18 and FGFR2 demonstrate the most prominent driving role in gastric tumorigenesis with gene amplification or somatic mutations and serve as prognostic biomarkers. FGF-FGFR promotes tumor progression by crosstalking with multiple oncogenic pathways and this provides a rational therapeutic strategy by co-targeting the crosstalks to achieve synergistic effects. In this review, we comprehensively summarize the pathogenic mechanisms of FGF-FGFR signaling in gastric adenocarcinoma together with the current targeted strategies in aberrant FGF-FGFR activated GC cases.
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Affiliation(s)
- Jinglin Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
| | - Patrick M K Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
| | - Yuhang Zhou
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
| | - Alfred S L Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, 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, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, 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, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
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32
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Koga Y, Ochiai A. Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors. Cells 2019; 8:cells8050418. [PMID: 31064068 PMCID: PMC6562882 DOI: 10.3390/cells8050418] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 04/26/2019] [Accepted: 05/04/2019] [Indexed: 01/06/2023] Open
Abstract
Patient-derived xenograft (PDX) models are used as powerful tools for understanding cancer biology in PDX clinical trials and co-clinical trials. In this systematic review, we focus on PDX clinical trials or co-clinical trials for drug development in solid tumors and summarize the utility of PDX models in the development of anti-cancer drugs, as well as the challenges involved in this approach, following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Recently, the assessment of drug efficacy by PDX clinical and co-clinical trials has become an important method. PDX clinical trials can be used for the development of anti-cancer drugs before clinical trials, with their efficacy assessed by the modified response evaluation criteria in solid tumors (mRECIST). A few dozen cases of PDX models have completed enrollment, and the efficacy of the drugs is assessed by 1 × 1 × 1 or 3 × 1 × 1 approaches in the PDX clinical trials. Furthermore, co-clinical trials can be used for personalized care or precision medicine with the evaluation of a new drug or a novel combination. Several PDX models from patients in clinical trials have been used to assess the efficacy of individual drugs or drug combinations in co-clinical trials.
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Affiliation(s)
- Yoshikatsu Koga
- Department of Strategic Programs, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan.
| | - Atsushi Ochiai
- Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan.
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33
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Ghanaatgar-Kasbi S, Khorrami S, Avan A, Aledavoud SA, Ferns GA. Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma. Curr Pharm Des 2019; 24:4619-4625. [PMID: 30636579 DOI: 10.2174/1381612825666190110145855] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 02/06/2023]
Abstract
The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various
cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple
malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become
a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in
the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting,
including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653),
Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV-
299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.
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Affiliation(s)
- Sadaf Ghanaatgar-Kasbi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shadi Khorrami
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed A. Aledavoud
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A. Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
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Okuno T, Yashiro M, Masuda G, Togano S, Kuroda K, Miki Y, Hirakawa K, Ohsawa M, Wanibuchi H, Ohira M. Establishment of a New Scirrhous Gastric Cancer Cell Line with FGFR2 Overexpression, OCUM-14. Ann Surg Oncol 2019; 26:1093-1102. [PMID: 30652228 DOI: 10.1245/s10434-018-07145-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND The prognosis of scirrhous gastric carcinoma (SGC), which is characterized by rapid infiltration and proliferation of cancer cells accompanied by extensive stromal fibrosis, is extremely poor. In this study, we report the establishment of a unique SGC cell line from a gastric cancer patient in whom an autopsy was performed. METHODS A new SGC cell line, OCUM-14, was established from malignant ascites of a male patient with SGC. A postmortem autopsy was performed on the patient. Characterization of OCUM-14 cells was analyzed by microscopic examination, reverse transcription polymerase chain reaction, fluorescence in situ hybridization analysis, immunohistochemical examination, CCK-8 assay, and in vivo assay. RESULTS OCUM-14 cells grew singly or in clusters, and were floating and round-shaped. Most OCUM-14 cells had many microvilli on their surfaces. The doubling time was 43.1 h, and the subcutaneous inoculation of 1.0 × 107 OCUM-14 cells into mice resulted in 50% tumor formation. mRNA expressions of fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) were observed in OCUM-14 cells. FGFR2, but not HER2, overexpression was found in OCUM-14 cells. The heterogeneous overexpression of FGFR2 was also found in both the primary tumor and metastatic lesions of the peritoneum, lymph node, bone marrow, and lung of the patient. The FGFR2 inhibitors AZD4547 and BGJ398 significantly decreased the growth of OCUM-14 cells, while paclitaxel and 5-fluorouracil significantly decreased the proliferation of OCUM-14 cells, but cisplatin did not. CONCLUSION A new gastric cancer cell line, OCUM-14, was established from SGC and showed FGFR2 overexpression. OCUM-14 might be useful for elucidating the characteristic mechanisms of SGC and clarifying the effect of FGFR2 inhibitors on SGC.
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Affiliation(s)
- Tomohisa Okuno
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan.,Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Masakazu Yashiro
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan. .,Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan. .,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan.
| | - Go Masuda
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
| | - Shingo Togano
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan.,Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Kenji Kuroda
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan.,Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Yuichiro Miki
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan.,Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Kosei Hirakawa
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
| | - Masahiko Ohsawa
- Department of Diagnostic Pathology, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Hideki Wanibuchi
- Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Masaichi Ohira
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
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Rashed WM. C-MET as a potential target therapy toward personalized therapy in some pediatric tumors: An overview. Crit Rev Oncol Hematol 2018; 131:7-15. [DOI: 10.1016/j.critrevonc.2018.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/22/2018] [Indexed: 12/28/2022] Open
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Awasthi N, Schwarz MA, Zhang C, Schwarz RE. Augmentation of Nab-Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models. Mol Cancer Ther 2018; 17:2353-2364. [PMID: 30166402 DOI: 10.1158/1535-7163.mct-18-0489] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 08/07/2018] [Accepted: 08/22/2018] [Indexed: 12/29/2022]
Abstract
Gastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC; however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, whereas tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts. The mechanistic evaluation involved IHC and Immunoblot analysis in tumor samples. Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib. Nab-paclitaxel combination with nintedanib was most effective in improving animal survival, always greater than 300% over control. In cell-derived subcutaneous xenografts, nab-paclitaxel reduced tumor growth while all three antiangiogenic agents enhanced this effect, with nintedanib demonstrating the greatest inhibition. Furthermore, in GAC patient-derived xenografts the combination of nab-paclitaxel and nintedanib reduced tumor growth over single agents alone. Tumor tissue analysis revealed that ramucirumab and cabozantinib only reduced tumor vasculature, whereas nintedanib in addition significantly reduced tumor cell proliferation and increased apoptosis. Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy. Mol Cancer Ther; 17(11); 2353-64. ©2018 AACR.
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Affiliation(s)
- Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana. .,Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana
| | - Margaret A Schwarz
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana.,Department of Pediatrics, Indiana University School of Medicine, South Bend, Indiana
| | - Changhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Roderich E Schwarz
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana.,Goshen Center for Cancer Care, Goshen, Indiana
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The significance of scirrhous gastric cancer cell lines: the molecular characterization using cell lines and mouse models. Hum Cell 2018; 31:271-281. [PMID: 29876827 DOI: 10.1007/s13577-018-0211-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 05/10/2018] [Indexed: 12/12/2022]
Abstract
Scirrhous gastric cancer (SGC) exhibits aggressiveness of the rapid infiltrating tumor cells with abundant fibroblasts. Experimental studies using SGC cell lines have obtained useful information about this cancer. Our literature search divulged a total of 18 SGC cell lines; two cell lines were established from primary SGC and the other lines were established from a metastatic lesion of SGC. Fibroblast growth factor receptor 2 (FGFR2) and transforming growth factor-beta receptor (TβR) are linked to the rapid development of SGC. Cross-talk between the cancer cells and cancer-associated fibroblasts (CAFs) has been shown to contribute to the progression of SGC. Chemokine (C-X-C motif) receptor 1 (CXCR1) from SGC cells might be associated with the abundant CAFs in cancer microenvironments. The in vivo models established using SGC cell lines are expected to serve as a useful tool for the development of drugs such as FGFR2 inhibitors, TβR inhibitors, and CXCR1 inhibitors, which might be promising as SGC treatments. However, the number of available SGC cell lines is insufficient for the clarification of the entire biologic behavior of SGC. Since the mechanisms responsible for the characteristic aggressiveness of SGC are not fully elucidated, the establishment of new SGC cell lines could help clarify the biological behavior of SGC and contribute to its treatment.
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Díaz-Serrano A, Angulo B, Dominguez C, Pazo-Cid R, Salud A, Jiménez-Fonseca P, Leon A, Galan MC, Alsina M, Rivera F, Plaza JC, Paz-Ares L, Lopez-Rios F, Gómez-Martín C. Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive Advanced Gastric Cancer Treated with Trastuzumab. Oncologist 2018; 23:1092-1102. [PMID: 29700210 DOI: 10.1634/theoncologist.2017-0379] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 02/22/2018] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. CONCLUSION Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.
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Affiliation(s)
| | - Barbara Angulo
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Carolina Dominguez
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Roberto Pazo-Cid
- Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Antonieta Salud
- Medical Oncology Unit, Hospital Universitario Arnau de Vilanova, Lérida, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana Leon
- Medical Oncology Unit, Fundación Jimenez Diaz, Madrid, Spain
| | - Maria Carmen Galan
- Medical Oncology Department, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Alsina
- Medical Oncology Department, Hospital Universitari Vall d'Hebrón, Barcelona, Spain
| | - Fernando Rivera
- Medical Oncology Deparment, Hospital Universitario Marques de Valdecilla, Santander, Spain
| | - J Carlos Plaza
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Luis Paz-Ares
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Fernando Lopez-Rios
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Carlos Gómez-Martín
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
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39
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Bajrami I, Marlow R, van de Ven M, Brough R, Pemberton HN, Frankum J, Song F, Rafiq R, Konde A, Krastev DB, Menon M, Campbell J, Gulati A, Kumar R, Pettitt SJ, Gurden MD, Cardenosa ML, Chong I, Gazinska P, Wallberg F, Sawyer EJ, Martin LA, Dowsett M, Linardopoulos S, Natrajan R, Ryan CJ, Derksen PWB, Jonkers J, Tutt ANJ, Ashworth A, Lord CJ. E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer. Cancer Discov 2018; 8:498-515. [PMID: 29610289 PMCID: PMC6296442 DOI: 10.1158/2159-8290.cd-17-0603] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 12/12/2017] [Accepted: 01/23/2018] [Indexed: 12/22/2022]
Abstract
The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients.Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin-defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498-515. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.
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Affiliation(s)
- Ilirjana Bajrami
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Rebecca Marlow
- The Breast Cancer Now Research Unit, King's College London, London, United Kingdom
| | - Marieke van de Ven
- Mouse Clinic for Cancer and Aging (MCCA) Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Rachel Brough
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Helen N Pemberton
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Jessica Frankum
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Feifei Song
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Rumana Rafiq
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Asha Konde
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Dragomir B Krastev
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Malini Menon
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - James Campbell
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Aditi Gulati
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Rahul Kumar
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Stephen J Pettitt
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Mark D Gurden
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Marta Llorca Cardenosa
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Biomedical Research Institute INCLIVA, Hospital Clinico Universitario Valencia, University of Valencia, Spain
| | - Irene Chong
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Patrycja Gazinska
- The Breast Cancer Now Research Unit, King's College London, London, United Kingdom
| | - Fredrik Wallberg
- FACS Core Facility, The Institute of Cancer Research, London, United Kingdom
| | - Elinor J Sawyer
- Division of Cancer Studies, Guy's Hospital, King's College London, London, United Kingdom
| | - Lesley-Ann Martin
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Mitch Dowsett
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Spiros Linardopoulos
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom
| | - Rachael Natrajan
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Colm J Ryan
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Patrick W B Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jos Jonkers
- Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Andrew N J Tutt
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom
- The Breast Cancer Now Research Unit, King's College London, London, United Kingdom
| | - Alan Ashworth
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
| | - Christopher J Lord
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
- Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
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Kim S, Barzi A, Rajdev L. Biomarker-driven targeted therapies for gastric/gastro-esophageal junction malignancies. Semin Oncol 2018; 45:133-150. [PMID: 30262395 DOI: 10.1053/j.seminoncol.2018.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 09/13/2017] [Accepted: 03/07/2018] [Indexed: 02/08/2023]
Abstract
Gastroesophageal malignancies often contain high amounts of genetic and molecular alterations that result in an aggressive disease capable of rapidly metastasizing to distant organs and early development of drug resistance. Most patients in the Western hemisphere present with locally advanced or metastatic disease that is treated with systemic chemotherapy used either in the neoadjuvant or palliative setting, respectively. This article will review the various recent advances in the development of targeted therapies for the treatment of advanced gastric and gastroesophageal cancer.
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Affiliation(s)
- Salem Kim
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY
| | - Afsaneh Barzi
- Keck School of Medicine at University of Southern California
| | - Lakshmi Rajdev
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
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41
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The multiple paths towards MET receptor addiction in cancer. Oncogene 2018; 37:3200-3215. [PMID: 29551767 DOI: 10.1038/s41388-018-0185-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/30/2018] [Accepted: 01/30/2018] [Indexed: 12/14/2022]
Abstract
Targeted therapies against receptor tyrosine kinases (RTKs) are currently used with success on a small proportion of patients displaying clear oncogene activation. Lung cancers with a mutated EGFR provide a good illustration. The efficacy of targeted treatments relies on oncogene addiction, a situation in which the growth or survival of the cancer cells depends on a single deregulated oncogene. MET, a member of the RTK family, is a promising target because it displays many deregulations in a broad panel of cancers. Although clinical trials having evaluated MET inhibitors in large populations have yielded disappointing results, many recent case reports suggest that MET inhibition may be effective in a subset of patients with unambiguous MET activation and thus, most probably, oncogene addiction. Interestingly, preclinical studies have revealed a particularity of MET addiction: it can arise through several mechanisms, and the mechanism involved can differ according to the cancer type. The present review describes the different mechanisms of MET addiction and their consequences for diagnosis and therapeutic strategies. Although in each cancer type MET addiction affects a restricted number of patients, pooling of these patients across all cancer types yields a targetable population liable to benefit from addiction-targeting therapies.
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Chen X, Guan Z, Lu J, Wang H, Zuo Z, Ye F, Huang J, Teng L. Synergistic antitumor effects of cMet inhibitor in combination with anti-VEGF in colorectal cancer patient-derived xenograft models. J Cancer 2018; 9:1207-1217. [PMID: 29675102 PMCID: PMC5907669 DOI: 10.7150/jca.20964] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 02/27/2018] [Indexed: 12/19/2022] Open
Abstract
cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. In this study, the expression of cMet in 146 Chinese colorectal cancer (CRC) patients was examined by immunohistochemistry staining. Our data demonstrated that cMet overexpression rate was 42.5% (62/146) and cMet overexpression was closely correlated with distant metastasis of CRC. Using CRC patient-derived xenograft (PDX) mouse models we investigated antitumor activity of a novel selective cMet inhibitor volitinib alone or in combination with anti-VEGF inhibitor apatinib in vivo. Our results showed that combination treatment significantly inhibited tumor growth in two PDX models. While volitinib treatment alone induced moderate improvement in tumor growth inhibition, combination treatment synergistically reduced microvessel density, suppressed proliferation, and increased apoptosis in PDX models. Further analysis showed synergistic inhibition of MAPK and PI3K/Akt pathways by volitinib and apatinib. Taken together, our data provide a rationale to targeting both cMet and VEGF in the treatment of cMet overexpressing CRC in clinical trials.
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Affiliation(s)
- Xiangheng Chen
- Department of Minimally Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China.,Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, P. R. China
| | - Zhonghai Guan
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Jun Lu
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Haohao Wang
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Zhongkun Zuo
- Department of Minimally Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Fei Ye
- Department of Minimally Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Jiangsheng Huang
- Department of Minimally Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
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Keller S, Zwingenberger G, Ebert K, Hasenauer J, Wasmuth J, Maier D, Haffner I, Schierle K, Weirich G, Luber B. Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines. Mol Oncol 2018; 12:441-462. [PMID: 29325228 PMCID: PMC5891041 DOI: 10.1002/1878-0261.12170] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 12/21/2017] [Accepted: 01/02/2018] [Indexed: 12/19/2022] Open
Abstract
The molecular mechanism of action of the HER2‐targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream‐acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI‐N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET‐amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
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Affiliation(s)
- Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Karolin Ebert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Jan Hasenauer
- Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Computational Biology, Neuherberg, Germany.,Department of Mathematical Modeling of Biological Systems, Center for Mathematics, Technische Universität München, Garching, Germany
| | - Jacqueline Wasmuth
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | | | | | - Katrin Schierle
- Institute of Pathology, Universitätsklinikum Leipzig, Germany
| | - Gregor Weirich
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
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Du J, Wu X, Tong X, Wang X, Wei J, Yang Y, Chang Z, Mao Y, Shao YW, Liu B. Circulating tumor DNA profiling by next generation sequencing reveals heterogeneity of crizotinib resistance mechanisms in a gastric cancer patient with MET amplification. Oncotarget 2018; 8:26281-26287. [PMID: 28460431 PMCID: PMC5432256 DOI: 10.18632/oncotarget.15457] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 02/04/2017] [Indexed: 12/18/2022] Open
Abstract
Crizotinib has been used to counter MET gene amplification in a number of different human malignancies. Transient response to crizotinib in MET-amplified gastric cancer has been reported, but the mechanisms of resistance are not well studied. Here, we reported a stage IV gastric cancer patient with high levels of MET amplification. The implementation of crizotinib treatment led to significant symptomatic improvement in the first 2 months, but was followed by rapid disease progression. Periodic mutation profiling of patient's circulating tumor DNA (ctDNA) by next generation sequencing (NGS) revealed a number of genetic alterations including re-occurrence of MET amplification, multiple secondary MET mutations, a dramatic increase of FGFR2 gene relative copy number as well as mutations in other downstream and bypassing elements, which may collectively related to the patient's cancer progression. Our results illustrate the complex and heterogeneous molecular mechanisms for crizotinib resistance in this patient, and demonstrate the great potential of ctDNA profiling for treatment decision-making and prognosis in clinical practice.
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Affiliation(s)
- Juan Du
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China
| | - Xue Wu
- Geneseeq Technology Inc., Toronto, Ontario, M5G1L7, Canada
| | - Xiaoling Tong
- Geneseeq Technology Inc., Toronto, Ontario, M5G1L7, Canada
| | - Xiaonan Wang
- Nanjing Geneseeq Technology Inc., Sino-Danish Life Science Park, Nanjing, Jiangsu, 210032, China
| | - Jia Wei
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China
| | - Yang Yang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China
| | - Zhili Chang
- Nanjing Geneseeq Technology Inc., Sino-Danish Life Science Park, Nanjing, Jiangsu, 210032, China
| | - Yu Mao
- Nanjing Geneseeq Technology Inc., Sino-Danish Life Science Park, Nanjing, Jiangsu, 210032, China
| | - Yang W Shao
- Geneseeq Technology Inc., Toronto, Ontario, M5G1L7, Canada
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China
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45
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Prognostic impact of fibroblast growth factor receptor 2 gene amplification in patients receiving fluoropyrimidine and platinum chemotherapy for metastatic and locally advanced unresectable gastric cancers. Oncotarget 2018; 8:33844-33854. [PMID: 27802183 PMCID: PMC5464916 DOI: 10.18632/oncotarget.12953] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/22/2016] [Indexed: 12/15/2022] Open
Abstract
Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival.Sixteen of 327 patients (4.9%) exhibited FGFR2 amplification. The amplification group showed associations with age <65 years, Borrmann type 4 disease, poor performance status, poorly differentiated histology, extra-abdominal lymph node metastases, and bone metastases. The median overall survival (OS) and progression-free survival (PFS) were found to be 12.7 and 5.8 months, respectively. In univariate analysis, PFS did not differ between amplification and no amplification groups (hazard ratio [HR]=1.34, 95% confidence interval [CI]: 0.78-2.31, p=0.290), although the OS was significantly shorter in the amplification group (HR=1.92, 95% CI: 1.13-3.26, p=0.015). However, multivariate analysis indicated that FGFR2 amplification was not an independent prognostic factor for OS (HR=1.42, 95% CI: 0.77-2.61, p=0.261).Although FGFR2 amplification is associated with poorer OS, it does not appear to be an independent prognostic predictor in patients with advanced gastric cancer treated with palliative fluoropyrimidine and platinum chemotherapy.
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Park CK, Park JS, Kim HS, Rha SY, Hyung WJ, Cheong JH, Noh SH, Lee SK, Lee YC, Huh YM, Kim H. Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm. Oncotarget 2018; 7:72099-72112. [PMID: 27765925 PMCID: PMC5342148 DOI: 10.18632/oncotarget.12291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 09/17/2016] [Indexed: 12/12/2022] Open
Abstract
Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.
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Affiliation(s)
- Cheol Keun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji Soo Park
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyo Song Kim
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Min Huh
- YUMS-KRIBB Medical Convergence Research Institute, Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Chen J, Huang K, Chen Q, Deng C, Zhang J, Zhong Z. Tailor-Making Fluorescent Hyaluronic Acid Microgels via Combining Microfluidics and Photoclick Chemistry for Sustained and Localized Delivery of Herceptin in Tumors. ACS APPLIED MATERIALS & INTERFACES 2018; 10:3929-3937. [PMID: 29302970 DOI: 10.1021/acsami.7b15832] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Antibody therapeutics, though representing a most used biomedicine, suffers from poor in vivo stability, rapid degradation, and frequent injections. Here, we report that fluorescent hyaluronic acid microgels (HMGs) tailor-made by combining microfluidics and "tetrazole-alkene" photoclick chemistry enable sustained and localized delivery of Herceptin in ovarian tumors. HMGs were obtained with a defined size (25-50 μm), narrow size distribution, high stability, and strong green fluorescence. Notably, HMGs exhibited a remarkably high loading of proteins such as Herceptin and IgG with a loading efficiency exceeding 90% at a theoretical protein-loading content of 30 wt %. In vitro protein release experiments revealed a sustained and hyaluronidase (HAase)-dependent release of Herceptin from HMGs, in which 80.6% of Herceptin was released at 1 U/mL HAase in 10 days. The released Herceptin maintained its secondary structure and antitumor activity. In vivo imaging results demonstrated obviously better tumoral retention for Cy5-labeled Herceptin-loaded HMGs following subcutaneous (sc) injection than for the free-protein counterpart. Interestingly, sc injection of the Herceptin-loaded HMGs into SKOV-3 human ovarian tumor-bearing nude mice at a dose of 30 mg Herceptin equiv/kg induced nearly complete tumor suppression, which was significantly more effective than the sc or systemic injection of free Herceptin. These tailor-made fluorescent HMGs appeared as a robust injectable platform for sustained and localized delivery of therapeutic proteins.
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Affiliation(s)
- Jing Chen
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, People's Republic of China
| | - Ke Huang
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, People's Republic of China
| | - Qijun Chen
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, People's Republic of China
| | - Chao Deng
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, People's Republic of China
| | - Jian Zhang
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, People's Republic of China
| | - Zhiyuan Zhong
- Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, People's Republic of China
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48
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Frequent Coamplification of Receptor Tyrosine Kinase and Downstream Signaling Genes in Japanese Primary Gastric Cancer and Conversion in Matched Lymph Node Metastasis. Ann Surg 2018; 267:114-121. [DOI: 10.1097/sla.0000000000002042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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49
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Bahrami A, Shahidsales S, Khazaei M, Ghayour-Mobarhan M, Maftouh M, Hassanian SM, Avan A. C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. J Cell Physiol 2017; 232:2657-2673. [PMID: 28075018 DOI: 10.1002/jcp.25794] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2025]
Abstract
Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis, and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK-rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy.
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Affiliation(s)
- Afsane Bahrami
- Molecular Medicine Group, Department of Modern Sciences and Technology, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh Shahidsales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Neurogenic Inflammatory Research Center and Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Maftouh
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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50
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Kim Y, Cho MY, Kim J, Kim SN, Oh SC, Lee KA. Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients. Oncotarget 2017; 8:69888-69905. [PMID: 29050249 PMCID: PMC5642524 DOI: 10.18632/oncotarget.19435] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 06/20/2017] [Indexed: 12/14/2022] Open
Abstract
Recently, the Cancer Genome Atlas (TCGA) Research Network and Asian Cancer Research Group provided a new classification of gastric cancer (GC) to aid the development of biomarkers for targeted therapy and predict prognosis. We studied associations between genetically aberrant profiles of cancer-related genes, environmental factors, and histopathological features in 107 paired gastric tumor-non-tumor tissue GC samples. 6.5% of our GC cases were classified as the EBV subtype, 17.8% as the MSI subtype, 43.0% as the CIN subtype, and 32.7% as the GS subtype. The distribution of four GC subgroups based on the TCGA and our dataset were similar. The MSI subtype showed a hyper-mutated status and the best prognosis among molecular subtype. However, molecular classification based on the four GC subtypes showed no significant survival differences in terms of overall survival (p= 0.548) or relapse-free survival (RFS, p=0.518). The P619fs*43 in ZBTB20 was limited to MSI group (n= 5/19, 26.3%), showing similar trends observed in TCGA dataset. Genetic alterations of the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways were detected in 34.6% of GC cases (37 individual cases). We also found two cases with likely pathogenic variants (NM_004360.4: c. 2494 G>A, p.V832M) in the CDH1 gene. Here, we classified molecular subtypes of GC according to the TCGA system and provide a critical starting point for the design of more appropriate clinical trials based on a comprehensive analysis of genetic alterations in Korean GC patients.
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Affiliation(s)
- Yoonjung Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Mee-Yon Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Juwon Kim
- Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Sung Nam Kim
- Department of Pathology, Samkwang Medical Labotories, Seoul, Korea
| | - Seoung Chul Oh
- Department of Laboratory Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Kyung-A Lee
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
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