Dataset Information

Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation.

ABSTRACT: Targeted therapy is a rational and promising strategy for the treatment of advanced cancer. For the development of clinical agents targeting oncogenic signaling pathways, it is important to define the specificity of compounds to the target molecular pathway. Genome-wide transcriptomic analysis is an unbiased approach to evaluate the compound mode of action, but it is still unknown whether the analysis could be widely applicable to classify molecularly targeted anticancer agents. We comprehensively obtained and analyzed 129 transcriptomic datasets of cancer cells treated with 83 anticancer drugs or related agents, covering most clinically used, molecularly targeted drugs alongside promising inhibitors of molecular cancer targets. Hierarchical clustering and principal component analysis revealed that compounds targeting similar target molecules or pathways were clustered together. These results confirmed that the gene signatures of these drugs reflected their modes of action. Of note, inhibitors of oncogenic kinase pathways formed a large unique cluster, showing that these agents affect a shared molecular pathway distinct from classical antitumor agents and other classes of agents. The gene signature analysis further classified kinome-targeting agents depending on their target signaling pathways, and we identified target pathway-selective signature gene sets. The gene expression analysis was also valuable in uncovering unexpected target pathways of some anticancer agents. These results indicate that comprehensive transcriptomic analysis with our database (http://scads.jfcr.or.jp/db/cs/) is a powerful strategy to validate and re-evaluate the target pathways of anticancer compounds.

SUBMITTER: Mashima T

PROVIDER: S-EPMC4520644 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation.

Mashima Tetsuo T Ushijima Masaru M Matsuura Masaaki M Tsukahara Satomi S Kunimasa Kazuhiro K Furuno Aki A Saito Sakae S Kitamura Masami M Soma-Nagae Taeko T Seimiya Hiroyuki H Dan Shingo S Yamori Takao T Tomida Akihiro A

Cancer science 20150525 7

Targeted therapy is a rational and promising strategy for the treatment of advanced cancer. For the development of clinical agents targeting oncogenic signaling pathways, it is important to define the specificity of compounds to the target molecular pathway. Genome-wide transcriptomic analysis is an unbiased approach to evaluate the compound mode of action, but it is still unknown whether the analysis could be widely applicable to classify molecularly targeted anticancer agents. We comprehensive ...[more]

PMID: 25911996

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Project description:BackgroundAntipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network meta-analysis was to determine the efficacy of augmentation drugs for the treatment of schizophrenia.MethodsIn accordance with the PRISMA statement, the PubMed, Web of Science, Google Scholar, CENTRAL, clinical trial and EUDRACT databases were searched from inception to May 15th, 2023. To ensure the robustness of the results, only double-blind randomised controlled trials with a low risk of bias (measured by the Risk Of Bias v2 (ROB2) tool) were included. The studies were categorised according to the background regimen: participants were treated with risperidone, mixed antipsychotics or clozapine. A Bayesian network meta-analysis was conducted using a random effects model. PROSPERO register: CRD42023420964.FindingsA total of 44 trials (comprising 45 augmentation drugs and 3358 participants) were included in the analysis. One-third of the drugs (16 drugs) demonstrated significant efficacy vs. placebo for at least one outcome. The most notable effect sizes (ESs) were observed for the use of tropisetron (standard mean difference: -0.83 [95% interval confidence -1.12 to -0.55]), memantine (-0.50 [-0.66 to -0.32]) and minocycline (-0.56 [-0.72 to -0.39]) to treat negative symptoms among patients treated with risperidone (moderate-to-high ESs). Studies involving mixed antipsychotics yielded lower ESs (small-to-moderate). Sodium benzoate (-0.41 [-0.60 to -0.21]) and memantine (-0.23 [-0.36 to -0.11]) were found have significant effects on positive symptoms, while memantine demonstrated efficacy for negative symptoms (-0.32 [-0.45 to -0.19]) and general psychopathology (-0.32 [-0.44 to -0.20]). Studies focusing exclusively on patients treated with clozapine revealed that duloxetine produced the best results (negative symptoms: -1.12 [-1.35 to -0.91]). Sodium benzoate was the only augmentation drug that demonstrated efficacy in relieving persistent positive symptoms (-0.32 [-0.59 to -0.08]) among patients treated with clozapine. Treatment with clozapine in combination with antipsychotics yielded small-to-moderate ESs.InterpretationThe GRADE framework indicated that the quality of the evidence among the included studies was moderate, primarily due to the limited number of randomised controlled trials with a low risk of bias. Important drugs did not appear in these results due to insufficient low-risk-of-bias data for these medications. These results highlight new pathways for treating schizophrenia that should be incorporated into future guidelines after further validation.FundingNo funding.

Dataset Information

Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation.

Publications

Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation.

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