• Gastric cancer
• Immunotherapy
• Targeted therapy

• Humans
• Stomach Neoplasms/therapy
• Stomach Neoplasms/immunology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/etiology
• Immunotherapy/methods
• Molecular Targeted Therapy/methods
• Animals
• Receptor, ErbB-2/antagonists & inhibitors

• 82203609 National Natural Science Foundation of China

• CLDN18.2
• DKK-1
• HER-2
• PD-L1
• TIGIT
• esophageal cancer
• gastric cancer
• gastroesophageal tumors
• microsatellite instability
• molecular biomarkers

• CD10271101 Christian Doppler Laboratory for Personalized Immunotherapy

• Gastric cancer
• Hepatocyte growth factor
• Prognosis assessment
• Review
• Targeted therapy
• c-Met

• CAR-T cells
• cancer vaccines
• ctDNA
• immunological targets
• metastatic gastric cancer
• molecular targets

• Ferroptosis
• Gastric cancer
• Lipid metabolism
• Lipid peroxidation
• Systematic review

• First-line therapy
• Gastric cancer
• Immunotherapy
• Targeted therapy

• Humans
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/therapy
• Stomach Neoplasms/pathology
• Immunotherapy/methods
• Molecular Targeted Therapy/methods
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Randomized Controlled Trials as Topic

• cell line
• gastric cancer
• proto-oncogene protein c-met
• tumor
• tyrosine kinase inhibitors

• Humans
• Proto-Oncogene Proteins c-met/metabolism
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/genetics
• Cell Line, Tumor
• Animals
• Triazines/pharmacology
• Mice
• Xenograft Model Antitumor Assays
• Benzamides/pharmacology
• Cell Proliferation/drug effects
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/metabolism
• Signal Transduction/drug effects
• Mice, Nude
• Protein Kinase Inhibitors/pharmacology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Molecular Targeted Therapy
• Female
• Imidazoles

• 03-2020-3 Boramae Medical Center

• copy number variation
• paclitaxel
• phosphorylated MET
• ramucirumab
• tepotinib

• Humans
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized/pharmacology
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• DNA Copy Number Variations
• Paclitaxel
• Phosphorylation
• Piperidines
• Pyridazines
• Pyrimidines
• Ramucirumab
• Stomach Neoplasms/drug therapy
• Proto-Oncogene Proteins c-met/genetics
• Proto-Oncogene Proteins c-met/metabolism

• HA17C0054 the National Research and Development Program for Cancer Control
• HI22C1375 the Korea Health Technology R&D Project
• 0000 the Hallym University Research Fund

• MET amplification
• gastric cancer
• heterogeneity
• pulmonary lymphangitis carcinomatosis
• targeted therapy

• Female
• Humans
• Lung/pathology
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/diagnosis
• Lymphangitis/etiology
• Lymphangitis/diagnosis
• Lymphangitis/pathology
• Prognosis
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Carcinoma

• Beijing Municipal Natural Science Foundation
• Fundamental Research Funds for the Central Universities
• National Natural Science Foundation of China

• Gastric cancer
• Immunotherapy
• Perioperative chemotherapy
• Targeted therapy

• 82203678 National Natural Science Foundation of China
• 2019-I2M-5-036 CAMS Innovation Fund for Medical Sciences
• 2019B020227002 Science and Technology Program of Guangdong Province, China

• Biomarker
• Gastric cancer
• Immune checkpoint inhibitor
• Precision medicine
• Receptor tyrosine kinase

In recent years, advances of anticancer and supportive therapies have determined a gradual improvement in survival rates and patients’ general conditions in metastatic gastric cancer (mGC), allowing them to receive further treatments. The choice of treatment is driven by performance status, age, stage of disease, number of metastatic sites and time from the first to third line of treatment. Targets such as microsatellite instability, PD-L1 expression, and HER2 overexpression or amplification may be addressed to personalise treatment and prolong survival. Despite a growing number of third line options that have provided clinicians with greater opportunities to customise treatments, up to date few agents have been demonstrated as effective after two standard lines for mGC; for these reasons, chemotherapy, immunotherapy, and targeted therapy were all widely investigated in both phase II and phase III studies. Overall, TAS-102, apatinib, regorafenib, nilotinib, trastuzumab, and pembrolizumab were demonstrated to be valid options in the third line scenario for mGC patient refractory to at least two lines of therapy. A multimodal approach based on chemotherapy, immunotherapy, targeted agents, a personalised nutritional programme as well as the research of new predictive biomarkers may pave the way to new strategies to identify the best treatment for each patient.

Fibroblast growth factor (FGF) and its receptor (FGFR) play crucial roles in gastric cancer (GC). Long non-coding RNAs (lncRNAs) are defined as RNA molecules of around 200 nucleotides or more, which are not translated into proteins. As well-known regulatory factors, lncRNAs are considered as biomarkers for prognosis and treatment response in GC. It is of importance to identify FGF/FGFR-related lncRNAs in GC. Here, some FGF/FGFR-related lncRNAs were identified in GC based on the data from public databases, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Then a four-lncRNAs (FGF10-AS1, MIR2052HG, POU6F2-AS2, and DIRC1) risk score (RS) model was established for predicting GC’s prognosis by using Cox analysis. According to the median value of RS, GC patients were divided into low and high RS group. Low RS group displayed high tumor mutation burden and infiltration of immune cells, as well as more sensitivity to immunotherapy or chemotherapy. High RS group showed high infiltration of stromal cells and more oncogenic signatures. In addition, a comprehensive analysis was carried out and found that high RS group may exhibit specific sensitivity to Panobinostat (histone deacetylases inhibitor) and Tivantinib (MET inhibitor). In summary, our study not only offers a novel personalized prognostication classification model according to FGF/FGFR-related lncRNAs, but also provides a new strategy for subclass-specific precision treatment in GC.

• Wenzhou Municipal Science and Technology Bureau

At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.

• MET amplification
• MET inhibition
• oncogenic driver mutations
• targeted therapy

• MET inhibitor
• adverse event
• hepatocellular carcinoma
• therapeutic effect
• tivantinib

Accurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC).

MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET gene amplification was assessed by chromogenic in situ hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells in vitro and in vivo, and the underlying molecular mechanisms were analyzed by western blot.

MET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth in vitro and in vivo in MKN45 cells with MET and phosphorylated MET (pMET) high expressions via suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity.

MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.

• HER2
• MET expression
• advanced gastric cancer
• chemotherapy
• real-time

• Bevacizumab
• Phase 1 trial
• Solid tumors
• Tivantinib
• VEGF inhibition
• c-MET RTK inhibition

• Carcinoma, Squamous Cell/pathology
• Chemoradiotherapy
• Combined Modality Therapy
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/therapy
• Humans
• Neoplasm Recurrence, Local

• P30 CA008748 NCI NIH HHS
• NIH

• Benzotriazoles
• Cell growth inhibition
• Extrusion pump inhibition
• Microtubule targeting agents
• Molecular docking
• Tubulin

Elevated expression of multiple growth factors and receptors including c‐Met and VEGFR has been reported in gastric adenocarcinoma (GAC) and thus provides a potentially useful therapeutic target. The therapeutic efficacy of foretinib, a c‐Met/VEGFR2 inhibitor, was determined in combination with nanoparticle paclitaxel (NPT) in GAC. Animal studies were conducted in NOD/SCID mice in subcutaneous and peritoneal dissemination xenografts. The mechanism of action was assessed by Immunohistochemical and Immunoblot analyses. In c‐Met overexpressing MKN‐45 cell‐derived xenografts, NPT and foretinib demonstrated inhibition in tumour growth, while NPT plus foretinib showed additive effects. In c‐Met low‐expressing SNU‐1 or patient‐derived xenografts, the foretinib effect was smaller, while NPT had a similar effect compared with MKN‐45, as NPT plus foretinib still exhibited an additive response. Median mice survival was markedly improved by NPT (83%), foretinib (100%) and NPT plus foretinib (230%) in peritoneal dissemination xenografts. Subcutaneous tumour analyses exhibited that foretinib increased cancer cell death and decreased cancer cell proliferation and tumour vasculature. NPT and foretinib suppressed the proliferation of GAC cells in vitro and had additive effects in combination. Further, foretinib caused a dramatic decrease in phosphorylated forms of c‐Met, ERK, AKT and p38. Foretinib led to a decrease in Bcl‐2, and an increase in p27, Bax, Bim, cleaved PARP‐1 and cleaved caspase‐3. Thus, these findings highlight the antitumour impact of simultaneous suppression of c‐Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients’ survival.

• c-Met
• combination therapy
• foretinib
• gastric cancer
• nab-paclitaxel

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.

• HGF
• MET amplification
• MET over-expression
• gastric cancer
• monoclonal antibodies
• tyrosine kinase inhibitors

Numerous studies have indicated that abnormal activation of the HGF/c-Met signaling pathway can lead to cell proliferation, invasiveness, and metastasis of cancers of the digestive system. Moreover, overexpression of c-Met has been implicated in poor prognosis of patients with these forms of cancer, suggesting the possibility for HGF/c-Met axis as a potential therapeutic target. Despite the large number of clinical and preclinical trials worldwide, no significant positive success in the use of anti-HGF/c-Met treatments on cancers of the digestive system has been achieved. In this review, we summarize advanced development of clinical research on HGF/c-Met antibody and small-molecule c-Met inhibitors of cancers of the digestive system and provide a possible direction for future research.

• c-Met
• digestive system cancer
• hepatocyte growth factor
• inhibitors
• molecular targeted therapy

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c‐Met inhibitor tivantinib as second‐line treatment significantly prolonged progression‐free survival in a subpopulation whose tumor samples highly expressed c‐Met (MET‐high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. This randomized, double‐blind, placebo‐controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET‐high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice‐a‐day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression‐free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression‐free survival was 2.8 (95% confidence interval: 2.7‐2.9) and 2.3 (1.5‐2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52‐1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1‐11.6) and 8.5 (6.2‐11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58‐1.15). The most common tivantinib‐related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. (NCT02029157).

• biomarker
• c-Met
• clinical study
• hepatocellular carcinoma
• tivantinib

• C-met
• Gastric cancer
• Tivantinib
• VEGF

Glioblastoma, the most common and malignant glial tumor, often has poor prognosis. Tivantinib has shown its potential in treating c-Met-high carcinoma. No studies have explored whether tivantinib inhibits the development of glioblastoma.

The correlation between c-Met expression and clinicopathological characteristics of glioblastoma was investigated. U251 and T98MG glioblastoma cells treated with tivantinib, PI3K inhibitor (LY294002), PI3K activator (740 Y-P), and/or mammalian target of rapamycin (mTOR) inhibitor were subjected to MTT assay or colony formation assay to evaluate cell proliferation. The expression of mTOR signaling and caspase-3 in tivantinib-treated glioblastoma cells was differentially measured by western blotting.

In a group of Chinese patients, expression of c-Met was elevated with the size of glioblastoma, but not with the other clinicopathological characteristics, including gender, age, grade, IDH status, 1p/19q status, and Ki67 status. High dose of tivantinib (1 μmol/L) obviously repressed the proliferation and colony formation of U251 and T98MG glioblastoma cells, but low dose (0.1 μmol/L) of tivantinib failed to retard cell proliferation. Tivantinib blocked PI3K/Akt/mTOR signaling but did not change the expression of cleaved caspase-3. PI3K activator 740 Y-P (20 μmol/L) significantly rescued tivantinib-induced decrease of cell proliferation. Tivantinib (1 μmol/L) in combination with PI3K inhibitor LY294002 (0.5 μmol/L) and mTOR inhibitor rapamycin (0.1 nmol/L) largely inhibited the proliferation of glioblastoma cells.

c-MET inhibitor tivantinib blocks PIKE/Akt/mTOR signaling and hampers the proliferation of glioblastoma cells, which endows the drug a therapeutic effect.

To investigate the clinical significance of MET gene amplification in patients with gastric cancer in the palliative setting.

MET amplification was assessed using fluorescence in situ hybridization (FISH) in 50 patients and quantitative polymerase chain reaction (qPCR) in 326 patients; 259 patients treated with first-line fluoropyrimidine and platinum were included for survival analysis.

The results of FISH and qPCR indicated that the c-MET/CEP7 ratio was correlated with gene copy number. The optimal cutoff value for the copy number using qPCR to detect MET gene amplification with FISH was 5 (κ=0.778, P<0.001). Twenty-one out of 326 patients (6.4%) were identified asMET amplification with a copy number of >5 detected by qPCR. MET-amplified gastric cancer was associated with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≥2 (33.3% vs. 10.5% P=0.007), peritoneal metastasis (76.2% vs. 46.2%, P=0.008), and elevated bilirubin levels (28.6% vs. 7.3%, P=0.006). The median overall survival (OS) and progression-free survival (PFS) were 11.9 and 5.6 months, respectively. MET-amplified gastric cancer was not associated with survival outcomes [hazard ratio (HR)=0.68, 95% confidence interval (95% CI): 0.35−1.32, P=0.254 for PFS; HR=0.68, 95% CI: 0.35−1.32, P=0.251 for OS].

qPCR can be used to detect MET gene amplification. MET amplification was not a predictor of poor prognosis in patients with metastatic or unresectable gastric cancer.

• MET
• advanced gastric cancer
• amplification
• prognosis
• quantitative real-time polymerase chain reaction

This study aimed to investigate the prognostic value of volumetric parameters on ¹⁸F- fluoro-2-deoxy-D-glucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) in gastric-cancer patients, according to the expression status of c-MET (MET proto-oncogene, receptor tyrosine kinase), which was previously unclear.

The study included 61 patients with advanced gastric cancer. Data on the baseline ¹⁸F-FDG PET/CT, clinical-pathological information, progression-free survival (PFS), and overall survival (OS) were collected. The maximum standardized uptake value (SUV_max), peak SUV (SUV_peak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of gastric tumors in situ were measured on PET/CT. The expression status of c-MET was recorded based on immunohistochemical staining. Associations between the parameters on PET/CT and patients’ survival outcomes were analyzed in relation to expression status of c-MET.

Patients with positive c-MET expression had significantly shorter PFS (11.5 vs. 17.6 months, P = 0.039) and OS (17.0 vs. 24.3 months, P = 0.043), and had gastric tumors with a larger MTV (70.8 ± 53.11 vs. 41.1 ± 52.32, P = 0.034) and TLG (428.39 ± 442.95 vs. 205.7 ± 354.40, P = 0.039), compared with those with negative c-MET expression. However, SUV_max (9.6 ± 7.40 vs. 8.0 ± 4.91, P = 0.335) and SUV_peak (7.7 ± 5.99 vs. 6.62 ± 4.08, P = 0.438) were similar between these two patient groups. In patients with c-MET-positive tumors, MTV and TLG were independent factors in predicting patient OS after correction by distant metastasis (hazards ratio = 1.014 and 1.002, respectively; P = 0.024 and 0.027, respectively), while these associations were not significant in patients with c-MET-negative tumors.

Patients with c-MET-positive gastric cancer had higher MTV and TLG values compared to those with c-MET-negative gastric cancer. In patients with c-MET-positive gastric cancer, volumetric parameters on ¹⁸F-FDG PET/CT have prognostic value for patient overall survival.

• 18F-FDG
• 2-[18F] Fluoro-2-deoxy-D-glucose
• Gastric cancer
• Positron emission tomography/computed tomography (PET/CT)
• Prognosis

• EpCAM
• HGF
• Met
• bispecific antibody
• cancer

• Animals
• Antibodies, Bispecific/pharmacology
• Antineoplastic Agents, Immunological/pharmacology
• Cell Line, Tumor
• Epithelial Cell Adhesion Molecule/antagonists & inhibitors
• Epithelial Cell Adhesion Molecule/metabolism
• Hepatocyte Growth Factor/metabolism
• Humans
• Mice
• Neoplasms, Experimental/drug therapy
• Neoplasms, Experimental/metabolism
• Neoplasms, Experimental/pathology
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Proto-Oncogene Proteins c-met/metabolism
• Signal Transduction/drug effects
• Xenograft Model Antitumor Assays

The c-Met protein is a receptor tyrosine kinase involved in cell growth, proliferation, survival, and angiogenesis of several human tumors. Overexpression of c-Met has been found in gastric cancers and correlated with a poor prognosis. Indirubin is the active component of Danggui Longhui Wan, which is a traditional Chinese antileukemic recipe. In the present study, we tested the anti-cancer effects of an indirubin derivative, LDD-1937, on human gastric cancer cells SNU-638. When we performed the in vitro kinase assay against the c-Met activity, LDD-1937 inhibited the activity of c-Met. This result was confirmed by immunoblot and immunofluorescence of phosphorylated c-Met. Immunoblot analysis showed that LDD-1937 decreased the expression of the Erk1/2, STAT3, STAT5, and Akt, downstream proteins of c-Met. In addition, LDD-1937 reduced the cell viability and suppressed colony formation and migration of SNU-638 cells. Furthermore, LDD-1937 induced G₂/M phase arrest in the SNU-638 cells by decreasing the expression levels of cyclin B1 and CDC2. Cleaved-PARP, an apoptosis-related protein, was up-regulated in cells treated with LDD-1937. Overall, this study suggests that LDD-1937 may be a novel small-molecule with therapeutic potential for selectively inhibiting c-Met and c-Met downstream pathways in human gastric cancers overexpressing c-Met.

• Gastric cancer
• Indirubin
• LDD-1937
• c-Met

The aim of this study was to assess the efficacy and safety of concurrent apatinib and docetaxel therapy vs apatinib monotherapy as third- or subsequent-line treatment for advanced gastric adenocarcinoma (GAC).

Patients, who had received apatinib with or without docetaxel as third or more line therapy for advanced GAC, were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to minimize the potential confounding bias. Kaplan–Meier curve and log-rank test were used to analyze the survival. Prognostic factors were estimated by Cox regression. Adverse events (AEs) were evaluated using CTCAE 4.0.

Thirty-four patients received concurrent therapy, whereas 31 received monotherapy. The median progression-free survival (PFS) and overall survival (OS) in monotherapy and con-therapy groups were 2.5 and 4 months (P=0.002), 3.3 and 6 months (P=0.004), respectively. After PSM, the median PFS and OS in the con-therapy group were also superior to the monotherapy group (P=0.004 and P=0.017). Cox regression suggested that Eastern Cooperative Oncology Group performance status (ECOG PS; HR =2.437, 95% CI: 1.349–4.404, P=0.003), CA199 (HR =1.001, 95% CI: 1.000–1.002, P=0.016), and treatment options (HR =0.388, 95% CI: 0.222–0.679, P=0.001) had significant effects on OS. Grade 3/4 toxicities in the monotherapy and con-therapy groups were as follows: leukopenia (0% vs 8.8%), neutropenia (3.2% vs 2.9%), anemia (9.8% vs 8.8%), thrombocytopenia (6.4% vs 2.9%), proteinuria (3.2% vs 2.9%), aminotransferase (0% vs 11.8%), hyperbilirubinemia (9.8% vs 5.9%), hypertension (9.8% vs5.9%), hand–foot syndrome (3.2% vs 8.8%), nausea and vomiting (0% vs 11.8%), diarrhea (0% vs 5.9%), and fatigue (6.5% vs 2.9%).

Patients with advanced GAC benefit more from concurrent apatinib and docetaxel therapy than apatinib monotherapy.

• overall survival
• progression-free survival
• propensity score matching

The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.

• HGF
• c-MET
• digestive system cancers
• miRNA

• Adenocarcinoma
• Cancer
• Chemotherapy
• Gastric
• Oesophageal
• Salvage
• Third-line

• Biomarkers
• Erlotinib
• Non‐small cell lung cancer
• Proteomics
• Tivantinib

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Non-Small-Cell Lung/blood
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/mortality
• Disease Progression
• Drug Resistance, Neoplasm
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/genetics
• Erlotinib Hydrochloride/pharmacology
• Erlotinib Hydrochloride/therapeutic use
• Feasibility Studies
• Female
• Humans
• Lung Neoplasms/blood
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/mortality
• Male
• Middle Aged
• Neoplasm Staging
• Predictive Value of Tests
• Prognosis
• Prospective Studies
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Proteomics/instrumentation
• Pyrrolidinones/pharmacology
• Pyrrolidinones/therapeutic use
• Quinolines/pharmacology
• Quinolines/therapeutic use
• Reagent Kits, Diagnostic
• Retrospective Studies
• Young Adult

• ARQ-197
• Circulating tumor cells
• MET phosphorylation
• Tivantinib
• Topotecan

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.

• Cancer
• Castration resistant
• Prostate
• Tivantinib

• PF-2341066
• c-Met
• celecoxib
• cholangiocarcinoma
• cyclooxygenase-2
• hepatolithiasis

• Amplification
• Cancer
• MET
• Mutation
• Targeted therapy

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF‐cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co‐culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA.

• angiogenesis
• exosomes
• hepatocyte growth factor
• siRNA
• tumor therapy