Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Research Progress in Targeted Therapy for Esophageal Cancer

Esophageal cancer (EC) is a prevalent malignant tumor that affects the digestive system and is often linked to a poor prognosis. The absence of effective early screening methods results in the diagnosis of esophageal cancer (EC) patients at advanced or metastatic stages. While historically considered incurable, ongoing advancements in medical research have led to the integration of various treatment modalities as primary approaches for managing advanced endometrial cancer. These modalities include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Notably, the introduction of targeted therapy and immunotherapy has significantly enhanced the survival rates of individuals with EC. Immunotherapy has appeared as the predominant treatment for advanced esophageal cancer, while targeted therapy faces certain obstacles. Consequently, this review primarily focuses on the advancements in targeted therapy for esophageal cancer (EC), evaluating the effectiveness and safety of relevant medications, and aiming to provide guidance for the comprehensive management of EC based on current research findings.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.Targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent targets underscore their importance in overcoming GSC-mediated resistance.Various therapeutic agents,notably RNA inhibitor/short hairpin RNA(27.3%),inhibitors(e.g.,LY294002,NVP-BEZ235)(24.2%),and monoclonal antibodies(e.g.,cetuximab)(9.1%),demonstrate versatility in targeted therapies.among 20 studies(60.6%),the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance(51.5%),followed by reductions in carmustine resistance(9.1%)and doxorubicin resistance(3.0%),while resistance to RTR is reduced in 42.4%of studies.CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance,emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy

Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,synthesizing most cholesterol and fatty acids.Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment.Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors.Here,we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC.HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.

The AGH score is a predictor of disease-free survival and targeted therapy efficacy after liver transplantation in patients with hepatocellular carcinoma

Background:Liver transplantation(LT)is the“cure”therapy for patients with hepatocellular carcinoma(HCC).However,some patients encounter HCC recurrence after LT.Unfortunately,there is no effective methods to identify the LT patients who have high risk of HCC recurrence and would benefit from adjuvant targeted therapy.The present study aimed to establish a scoring system to predict HCC recurrence of HCC patients after LT among the Chinese population,and to evaluate whether these patients are suitable for adjuvant targeted therapy.Methods:Clinical data of HCC patients who underwent LT from March 2015 to June 2019 were retrospectively collected and analyzed.Results:A total of 201 patients were included in the study.The multivariate Cox analysis suggested that preoperative alpha-fetoprotein(AFP)>200μg/L(HR=2.666,95%CI:1.515-4.690;P=0.001),glutamyl transferase(GGT)>96 U/L(HR=1.807,95%CI:1.012-3.224;P=0.045),and exceeding the Hangzhou criteria(HR=2.129,95%CI:1.158-3.914;P=0.015)were independent risk factors for poor disease-free survival(DFS)in patients with HCC who underwent LT.We established an AFP-GGT-Hangzhou(AGH)scoring system based on these factors,and divided cases into high-,moderate-,and low-risk groups.The differences in overall survival(OS)and disease-free survival(DFS)rates among the three groups were significant(P<0.05).The efficacy of the AGH scoring system to predict DFS was better than that of the Hangzhou criteria,UCSF criteria,Milan criteria,and TNM stage.Only in the high-risk group,we found that lenvatinib significantly improved prognosis compared with that of the control group(P<0.05).Conclusions:The AGH scoring system provides a convenient and effective way to predict HCC recurrence after LT in HCC patients in China.Patients with a high-risk AGH score may benefit from lenvatinib adjuvant therapy after LT.

Pathogen detection in patients with perihilar cholangiocarcinoma:Implications for targeted perioperative antibiotic therapy

Background:Cholestasis should be relieved by biliary drainage prior to major liver resection.This condition is often associated with bacterial colonization of the otherwise sterile biliary system.Cholangitis reduces the regenerative capacity of the remaining liver.Therefore,targeted antibiotic therapy is a key feature in perioperative treatment in patients with perihilar cholangiocarcinoma(pCCC).Methods:Between December 1999 and December 2017,251 pCCC patients were treated in our center.In total,115 patients underwent a microbiological analysis.In addition to the characterization of the specific microorganisms and antibiotic resistance,we analyzed subgroups according to preoperative intervention.Results:Enterococci(87/254,34%)and Enterobacteria(65/254,26%)were the most frequently detected genera.In 43%(50/115)of patients,Enterococcus faecalis was found in the bile duct sample.Enterococcus faecium(29/115)and Escherichia coli(29/115)were detected in 25%of patients.In patients with percutaneous transhepatic biliary drainage(3/8,38%)or stents(24/79,30%),Enterococcus faecium was diagnosed most frequently(P<0.05).Enterococcus faecium and Klebsiella oxytoca were significantly more frequently noted in the time period after 2012(P<0.05).With regard to fungal colonization,the focus was on various Candida strains,but these strains generally lacked resistance.Conclusions:pCCC patients exhibit specific bacterial colonization features depending on the type of preoperative biliary intervention.Specifically,targeted antibiosis should be applied in this patient cohort to minimize the risk of biliary complications after major liver resection.In our cohort,the combination of meropenem and vancomycin represents an effective perioperative medical approach.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas

Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.

Predictive Value of Peripheral Blood Markers in Hepatocellular Carcinoma Patients Treated with Anti-PD-1 in Combination with Targeted Therapy

Background: There are currently no recognised biomarkers that identify predictive groups of benefit in patients with hepatocellular carcinoma receiving immune-combined targeted therapy, for which we explored the value of peripheral blood markers as markers of their prognosis. Methods: Patients who underwent anti-PD-1 combination targeted therapy for hepatocellular carcinoma from 1 January 2019 to 31 December 2021 at the First Affiliated Hospital of Chongqing Medical University were retrospectively analysed. The data collected were analysed by R software. Results: A total of 41 cases were included in our study. The optimal threshold values of peripheral blood markers were obtained by plotting ROC curves and grouping patients. Survival analysis of the grouped patients showed statistically significant differences in survival between the different groups for Platelet-lymphocyte ratio (PLR, P = 0.0022), Monocyte-lymphocyte ratio (MLR, P = 0.042), Fibrinogen-Lymphocyte Ratio (FLR, P = 0.0009), Prognostic nutritional index (PIN, P = 0.0005), and Fibrinogen-albumin ratio (FAR, P = 0.0144). An ANOVA was performed on the basic conditions of the patients between the different groups, except for the statistically significant difference in BCLC stage (P = 0.0128) between the high MLR and low MLR groups, there was no statistically significant difference in age, gender, BCLC stage, and hepatitis status between the groups. COX regression analysis showed that BCLC stage, FAR, FLR and PIN were risk factors associated with the prognosis of patients receiving targeted combination immunotherapy for hepatocellular carcinoma, and FLR was an independent risk factor associated with the prognosis of patients receiving targeted combination immunotherapy for hepatocellular carcinoma. Conclusions: We found that peripheral blood markers are promising biomarkers for predicting the prognosis of patients with hepatocellular carcinoma receiving anti-PD-1 combined with targeted therapy, and this study identified FLR as an independent risk factor for the prognosis of patients having advanced hepatocellular carcinoma treated with anti-PD-1 combined with targeted therapy.

Identification of genes associated with gall bladder cell carcinogenesis:Implications in targeted therapy of gall bladder cancer

Gall bladder cancer(GBC)is becoming a very devastating form of hepatobiliary cancer in India.Every year new cases of GBC are quite high in India.Despite recent advanced multimodality treatment options,the survival of GBC patients is very low.If the disease is diagnosed at the advanced stage(with local nodal metastasis or distant metastasis)or surgical resection is inoperable,the prognosis of those patients is very poor.So,perspectives of targeted therapy are being taken.Targeted therapy includes hormone therapy,proteasome inhibitors,signal transduction and apoptosis inhibitors,angiogenesis inhibitors,and immunotherapeutic agents.One such signal transduction inhibitor is the specific short interfering RNA(siRNA)or short hairpin RNA(shRNA).For developing siRNAmediated therapy shRNA,although several preclinical studies to evaluate the efficacy of these key molecules have been performed using gall bladder cells,many more clinical trials are required.To date,many such genes have been identified.This review will discuss the recently identified genes associated with GBC and those that have implications in its treatment by siRNA or shRNA.

Recent advances in targeted therapy for pancreatic adenocarcinoma

Pancreatic adenocarcinoma(PDAC)is a fatal disease with a 5-year survival rate of 8%and a median survival of 6 mo.In PDAC,several mutations in the genes are involved,with Kirsten rat sarcoma oncogene(90%),cyclin-dependent kinase inhibitor 2A(90%),and tumor suppressor 53(75%–90%)being the most common.Mothers against decapentaplegic homolog 4 represents 50%.In addition,the selfpreserving cancer stem cells,dense tumor microenvironment(fibrous accounting for 90%of the tumor volume),and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC.Molecular targeted therapy is widely utilized and effective in several solid tumors.In PDAC,targeted therapy has been extensively evaluated;however,survival improvement of this aggressive disease using a targeted strategy has been minimal.There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC–erlotinib,but the absolute benefit of erlotinib in combination with gemcitabine is also minimal(2 wk).In this review,we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process,analyze possible reasons for the lack of positive results in clinical trials,and suggest ways to improve them.We also discuss emerging trends in targeted therapies for PDAC:combining targeted inhibitors of multiple pathways.The PubMed database and National Center for Biotechnology Information clinical trial website(www.clinicaltrials.gov)were queried to identify completed and published(PubMed)and ongoing(clinicaltrials.gov)clinical trials(from 2003-2022)using the keywords pancreatic cancer and targeted therapy.The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.

Managing facial infiltrating lipomatosis associated with PIK3CA mutation:From surgery to targeted therapy

Facial infiltrating lipomatosis(FIL)is a congenital asymmetrical deformity of the maxillofacial region that can significantly affect a patient’s facial appearance and function.With the development of sequencing technologies,PIK3CA mutations are considered among the potential etiologies of FIL.The management and treatment of FIL involves plastic surgery;more recently,an improved understanding of its pathogenesis has given rise to new treatment options,including targeted therapy.Here we report the clinical data of two patients diagnosed with FIL and present current curative concepts.

Novel insights into mTOR signalling pathways: A paradigm for targeted tumor therapy

As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and disorders have been linked to imbalances in mTOR's regulatory systems.Multiple mTOR inhibitor therapy has recently acquired popularity as a method of treating cancers brought on by abnormal signal transduction pathways.We also explore potential processes behind tumor cell resistance to mTOR inhibitors and suggest workarounds to overcome this challenge.We hold the potential to pioneer cutting-edge methods for tumor therapy by methodically examining the complex mTOR signaling system and its regulatory complexity.Increasing our knowledge of mTOR-related mechanisms not only creates opportunities for cutting-edge methods to target and treat cancers but also has the potential to improve patient outcomes and general quality of life significantly.This review paper explores the most recent developments in understanding mTOR signaling pathways and the use of mTOR inhibitors in treating tumors.

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

Advances in radiotherapy and targeted therapies for rectal cancer

The last decade witnessed a significant progress in understanding the biology and immunology of colorectal cancer alongside with the technical innovations in radiotherapy.The stepwise implementation of intensitymodulated and image-guided radiation therapy by means of megavolt computed tomography and helical tomotherapy enabled us to anatomically sculpt dose delivery,reducing treatment related toxicity.In addition,the administration of a simultaneous integrated boost offers excellent local control rates.The novel challenge is the development of treatment strategies for medically inoperable patient and organ preserving approaches.However,distant control remains unsatisfactory and indicates an urgent need for biomarkers that predict the risk of tumor spread.The expected benefit of target?ed therapies that exploit the tumor genome alone is so far hindered by high cost techniques and pharmaceuticals,hence hardly justifying rather modest improvements in patient outcomes.On the other hand,the immune landscape of colorectal cancer is now better clarified with regard to the immunosuppressive network that promotes immune escape.Both N2 neutrophils and myeloid-derived suppressor cells(MDSC)emerge as useful clinical biomarkers of poor prognosis,while the growing list of anti-MDSC agents shows promising ability to boost antitumor T-cell immunity in preclinical settings.Therefore,integration of genetic and immune biomarkers is the next logical step towards effective targeted therapies in the context of personalized cancer treatment.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Role of autophagy in tumorigenesis,metastasis,targeted therapy and drug resistance of hepatocellular carcinoma

Autophagy is a "self-degradative" process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.

Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy

The incidence and mortality of hepatocellular carcinoma(HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics.

Molecular targeted therapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide.The majority of HCC cases occur in patients with chronic liver disease.Despite regular surveillance to detect small HCC in these patients,HCC is often diagnosed at an advanced stage.Because HCC is highly resistant to conventional systemic therapies,the prognosis for advanced HCC patients remains poor.The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment.However,given the limited efficacy of the drug,a need exists to look beyond sorafenib.Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development,and novel targets are being assessed in HCC.This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.

Targeted therapies in gastric cancer and future perspectives

Advanced gastric cancer(AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after firstline platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase Ⅰ-Ⅱ trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER(2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.