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Changing strategies for target therapy in gastric cancer.

ABSTRACT: In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.

SUBMITTER: Lee SY

PROVIDER: S-EPMC4716029 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Changing strategies for target therapy in gastric cancer.

Lee Suk-Young SY Oh Sang Cheul SC

World journal of gastroenterology 20160101 3

In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of ...[more]

PMID: 26811656

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Project description:UNLABELLED: BACKGROUND:Cancer therapy is a challenging research area because side effects often occur in chemo and radiation therapy. We intend to study a multi-targets and multi-components design that will provide synergistic results to improve efficiency of cancer therapy. METHODS:We have developed a general methodology, AMFES (Adaptive Multiple FEature Selection), for ranking and selecting important cancer biomarkers based on SVM (Support Vector Machine) classification. In particular, we exemplify this method by three datasets: a prostate cancer (three stages), a breast cancer (four subtypes), and another prostate cancer (normal vs. cancerous). Moreover, we have computed the target networks of these biomarkers as the signatures of the cancers with additional information (mutual information between biomarkers of the network). Then, we proposed a robust framework for synergistic therapy design approach which includes varies existing mechanisms. RESULTS:These methodologies were applied to three GEO datasets: GSE18655 (three prostate stages), GSE19536 (4 subtypes breast cancers) and GSE21036 (prostate cancer cells and normal cells) shown in. We selected 96 biomarkers for first prostate cancer dataset (three prostate stages), 72 for breast cancer (luminal A vs. luminal B), 68 for breast cancer (basal-like vs. normal-like), and 22 for another prostate cancer (cancerous vs. normal. In addition, we obtained statistically significant results of mutual information, which demonstrate that the dependencies among these biomarkers can be positive or negative. CONCLUSIONS:We proposed an efficient feature ranking and selection scheme, AMFES, to select an important subset from a large number of features for any cancer dataset. Thus, we obtained the signatures of these cancers by building their target networks. Finally, we proposed a robust framework of synergistic therapy for cancer patients. Our framework is not only supported by real GEO datasets but also aim to a multi-targets/multi-components drug design tool, which improves the traditional single target/single component analysis methods. This framework builds a computational foundation which can provide a clear classification of cancers and lead to an efficient cancer therapy.

Project description:BackgroundExosomes are critically involved in cancer development and progression. The exosomal contents have been suggested as ideal cancer biomarkers. In this study, we investigated the expression of exosomal proteins in the serum of gastric cancer patients and their roles in gastric cancer.MethodsThe proteomic profile of exosomes from the serum of gastric cancer patients was detected by using LC-MS/MS. The expression of TRIM3 in exosomes from the serum of gastric cancer patients and healthy controls was assessed by ELISA and western blot. Immunohistochemistry was used to detect TRIM3 expression in gastric cancer tissues and their matching adjacent tissues. The growth and migration abilities of gastric cancer cells with TRIM3 overexpression or knockdown in vitro were evaluated by colony formation assay and transwell migration assay. The effects of TRIM3 overexpression or knockdown on gastric cancer growth and metastasis in vivo were investigated by using subcutaneous xenograft tumor and peritoneal metastasis mouse model. The effects of TRIM3-overexpressing exosomes on gastric cancer growth and metastasis in vitro and in vivo were also evaluated.ResultsWe found that the expression levels of TRIM3 mRNA and protein were decreased in gastric cancer tissues compared to the matched control tissues. In addition, the levels of TRIM3 protein in the serum exosomes of gastric cancer patients were lower than that in healthy controls. We demonstrated that TRIM3 overexpression reduced while TRIM3 knockdown promoted the growth and metastasis of gastric cancer in vitro and in vivo through the regulation of stem cell factors and EMT regulators. Moreover, exosomes-mediated delivery of TRIM3 protein could suppress gastric cancer growth and metastasis in vitro and in vivo.ConclusionsTaken together, our findings suggest that exosomal TRIM3 may serve as a biomarker for gastric cancer diagnosis and the delivery of TRIM3 by exosomes may provide a new avenue for gastric cancer therapy.

Project description:BackgroundGastric cancer is the second most common cause of cancer-related deaths worldwide. There are large geographic variations in the incidence of these tumors, with 60% occurring in East Asia. For patients with resectable disease, surgery and perioperative treatment can be effective. For patients with advanced gastric cancer, chemotherapy regimens result in a median survival of 9-11 months. In general, the prognosis for advanced disease is poor and 5-year overall survival rates are around 15%. Combination therapies yield better survival rates, albeit with increased toxicity. Therefore, more effective and less toxic treatment regimens are needed.SummaryThe molecular aberrations that characterize the different subgroups of gastric cancer have been used as therapeutic targets. However, the heterogeneity and complexity of gastric cancers is a major challenge for the development of effective targeted therapies. This review examines the main molecular targets in the treatment of gastric cancer, namely the vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor (HGF)/c-Met, epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K)/Akt pathways.Key messageThe molecular aberrations characteristic of gastric cancer are being explored for the development of targeted therapies, including the VEGF, HER2, HGF/c-Met, EGFR and PI3K/Akt signaling pathways.Practical implicationsTrastuzumab, an antibody which targets HER2, is the first approved targeted therapy for the treatment of gastric cancer. However, trastuzumab is only effective in HER2-positive tumors (about 10-20% of all gastric cancers). Ramucirumab, which targets the VEGF receptor 2, has yielded benefits with respect to overall survival in a phase III trial and is an effective treatment for advanced gastric cancer with approval in second-line treatment. Apatinib and rilotumumab are another two promising new agents currently under development.

Dataset Information

Changing strategies for target therapy in gastric cancer.

Publications

Changing strategies for target therapy in gastric cancer.

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