Predicting Drug Response and Synergy Using a Deep Learning Model of Human Cancer Cells.
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ABSTRACT:
SUBMITTER: Kuenzi BM
PROVIDER: S-EPMC7737474 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Motivation:While drug combination therapies are a well-established concept in cancer treatment, identifying novel synergistic combinations is challenging due to the size of combinatorial space. However, computational approaches have emerged as a time- and cost-efficient way to prioritize combinations to test, based on recently available large-scale combination screening data. Recently, Deep Learning has had an impact in many research areas by achieving new state-of-the-art model performance. However, Deep Learning has not yet been applied to drug synergy prediction, which is the approach we present here, termed DeepSynergy. DeepSynergy uses chemical and genomic information as input information, a normalization strategy to account for input data heterogeneity, and conical layers to model drug synergies. Results:DeepSynergy was compared to other machine learning methods such as Gradient Boosting Machines, Random Forests, Support Vector Machines and Elastic Nets on the largest publicly available synergy dataset with respect to mean squared error. DeepSynergy significantly outperformed the other methods with an improvement of 7.2% over the second best method at the prediction of novel drug combinations within the space of explored drugs and cell lines. At this task, the mean Pearson correlation coefficient between the measured and the predicted values of DeepSynergy was 0.73. Applying DeepSynergy for classification of these novel drug combinations resulted in a high predictive performance of an AUC of 0.90. Furthermore, we found that all compared methods exhibit low predictive performance when extrapolating to unexplored drugs or cell lines, which we suggest is due to limitations in the size and diversity of the dataset. We envision that DeepSynergy could be a valuable tool for selecting novel synergistic drug combinations. Availability and implementation:DeepSynergy is available via www.bioinf.jku.at/software/DeepSynergy. Contact:klambauer@bioinf.jku.at. Supplementary information:Supplementary data are available at Bioinformatics online.
| S-EPMC5925774 | biostudies-literature
Project description:MotivationCancer heterogeneity drastically affects cancer therapeutic outcomes. Predicting drug response in vitro is expected to help formulate personalized therapy regimens. In recent years, several computational models based on machine learning and deep learning have been proposed to predict drug response in vitro. However, most of these methods capture drug features based on a single drug description (e.g. drug structure), without considering the relationships between drugs and biological entities (e.g. target, diseases, and side effects). Moreover, most of these methods collect features separately for drugs and cell lines but fail to consider the pairwise interactions between drugs and cell lines.ResultsIn this paper, we propose a deep learning framework, named MSDRP for drug response prediction. MSDRP uses an interaction module to capture interactions between drugs and cell lines, and integrates multiple associations/interactions between drugs and biological entities through similarity network fusion algorithms, outperforming some state-of-the-art models in all performance measures for all experiments. The experimental results of de novo test and independent test demonstrate the excellent performance of our model for new drugs. Furthermore, several case studies illustrate the rationality for using feature vectors derived from drug similarity matrices from multisource data to represent drugs and the interpretability of our model.Availability and implementationThe codes of MSDRP are available at https://github.com/xyzhang-10/MSDRP.
| S-EPMC10474952 | biostudies-literature
Project description:Rapidly developing single-cell sequencing analyses produce more comprehensive profiles of the genomic, transcriptomic, and epigenomic heterogeneity of tumor subpopulations than do traditional bulk sequencing analyses. Moreover, single-cell techniques allow the response of a tumor to drug exposure to be more thoroughlyinvestigated. Deep learning (DL) models have successfully extracted features from complex bulk sequence data to predict drug responses. We review recent innovations in single-cell technologies and DL-based approaches related to drug sensitivity predictions. We believe that, by using insights from bulk sequencedata, deep transfer learning (DTL) can facilitate the use of single-cell data for training superior DL-based drug prediction models.
| S-EPMC7669610 | biostudies-literature
Project description:While synergistic drug combinations are more effective at fighting tumors with complex pathophysiology, preference compensating mechanisms, and drug resistance, the identification of novel synergistic drug combinations, especially complex higher-order combinations, remains challenging due to the size of combination space. Even though certain computational methods have been used to identify synergistic drug combinations in lieu of traditional in vitro and in vivo screening tests, the majority of previously published work has focused on predicting synergistic drug pairs for specific types of cancer and paid little attention to the sophisticated high-order combinations. The main objective of this study is to develop a deep learning-based approach that integrated multi-omics data to predict novel synergistic multi-drug combinations (DeepMDS) in a given cell line. To develop this approach, we firstly created a dataset comprising of gene expression profiles of cancer cell lines, target information of anti-cancer drugs, and drug response against a large variety of cancer cell lines. Based on the principle of a fully connected feed forward Deep Neural Network, the proposed model was constructed using this dataset, which achieved a high performance with a Mean Square Error (MSE) of 2.50 and a Root Mean Squared Error (RMSE) of 1.58 in the regression task, and gave the best classification accuracy of 0.94, an area under the Receiver Operating Characteristic curve (AUC) of 0.97, a sensitivity of 0.95, and a specificity of 0.93. Furthermore, we utilized three breast cancer cell subtypes (MCF-7, MDA-MD-468 and MDA-MB-231) and one lung cancer cell line A549 to validate the predicted results of our model, showing that the predicted top-ranked multi-drug combinations had superior anti-cancer effects to other combinations, particularly those that were widely used in clinical treatment. Our model has the potential to increase the practicality of expanding the drug combinational space and to leverage its capacity to prioritize the most effective multi-drug combinational therapy for precision oncology applications.
| S-EPMC9797718 | biostudies-literature
Project description:BACKGROUND:Adverse drug reactions (ADRs) are unintended and harmful reactions caused by normal uses of drugs. Predicting and preventing ADRs in the early stage of the drug development pipeline can help to enhance drug safety and reduce financial costs. METHODS:In this paper, we developed machine learning models including a deep learning framework which can simultaneously predict ADRs and identify the molecular substructures associated with those ADRs without defining the substructures a-priori. RESULTS:We evaluated the performance of our model with ten different state-of-the-art fingerprint models and found that neural fingerprints from the deep learning model outperformed all other methods in predicting ADRs. Via feature analysis on drug structures, we identified important molecular substructures that are associated with specific ADRs and assessed their associations via statistical analysis. CONCLUSIONS:The deep learning model with feature analysis, substructure identification, and statistical assessment provides a promising solution for identifying risky components within molecular structures and can potentially help to improve drug safety evaluation.
| S-EPMC6300887 | biostudies-other
Project description:Advancing precision oncology requires accurate prediction of treatment response and accessible prediction models. To this end, we present shinyDeepDR, a user-friendly implementation of our innovative deep learning model, DeepDR, for predicting anti-cancer drug sensitivity. The web tool makes DeepDR more accessible to researchers without extensive programming experience. Using shinyDeepDR, users can upload mutation and/or gene expression data from a cancer sample (cell line or tumor) and perform two main functions: "Find Drug," which predicts the sample's response to 265 approved and investigational anti-cancer compounds, and "Find Sample," which searches for cell lines in the Cancer Cell Line Encyclopedia (CCLE) and tumors in The Cancer Genome Atlas (TCGA) with genomics profiles similar to those of the query sample to study potential effective treatments. shinyDeepDR provides an interactive interface to interpret prediction results and to investigate individual compounds. In conclusion, shinyDeepDR is an intuitive and free-to-use web tool for in silico anti-cancer drug screening.
| S-EPMC10873157 | biostudies-literature
Project description:BackgroundBreast cancer is the most common malignancy among women worldwide. Despite advances in treating breast cancer over the past decades, drug resistance and adverse effects remain challenging. Recent therapeutic progress has shifted toward using drug combinations for better treatment efficiency. However, with a growing number of potential small-molecule cancer inhibitors, in silico strategies to predict pharmacological synergy before experimental trials are required to compensate for time and cost restrictions. Many deep learning models have been previously proposed to predict the synergistic effects of drug combinations with high performance. However, these models heavily relied on a large number of drug chemical structural fingerprints as their main features, which made model interpretation a challenge.ResultsThis study developed a deep neural network model that predicts synergy between small-molecule pairs based on their inhibitory activities against 13 selected key proteins. The synergy prediction model achieved a Pearson correlation coefficient between model predictions and experimental data of 0.63 across five breast cancer cell lines. BT-549 and MCF-7 achieved the highest correlation of 0.67 when considering individual cell lines. Despite achieving a moderate correlation compared to previous deep learning models, our model offers a distinctive advantage in terms of interpretability. Using the inhibitory activities against key protein targets as the main features allowed a straightforward interpretation of the model since the individual features had direct biological meaning. By tracing the synergistic interactions of compounds through their target proteins, we gained insights into the patterns our model recognized as indicative of synergistic effects.ConclusionsThe framework employed in the present study lays the groundwork for future advancements, especially in model interpretation. By combining deep learning techniques and target-specific models, this study shed light on potential patterns of target-protein inhibition profiles that could be exploited in breast cancer treatment.
| S-EPMC10905801 | biostudies-literature
Project description:Radiographic imaging is routinely used to evaluate treatment response in solid tumors. Current imaging response metrics do not reliably predict the underlying biological response. Here, we present a multi-task deep learning approach that allows simultaneous tumor segmentation and response prediction. We design two Siamese subnetworks that are joined at multiple layers, which enables integration of multi-scale feature representations and in-depth comparison of pre-treatment and post-treatment images. The network is trained using 2568 magnetic resonance imaging scans of 321 rectal cancer patients for predicting pathologic complete response after neoadjuvant chemoradiotherapy. In multi-institution validation, the imaging-based model achieves AUC of 0.95 (95% confidence interval: 0.91-0.98) and 0.92 (0.87-0.96) in two independent cohorts of 160 and 141 patients, respectively. When combined with blood-based tumor markers, the integrated model further improves prediction accuracy with AUC 0.97 (0.93-0.99). Our approach to capturing dynamic information in longitudinal images may be broadly used for screening, treatment response evaluation, disease monitoring, and surveillance.
| S-EPMC7994301 | biostudies-literature
Project description:Chromatin contacts between regulatory elements are of crucial importance for the interpretation of transcriptional regulation and the understanding of disease mechanisms. However, existing computational methods mainly focus on the prediction of interactions between enhancers and promoters, leaving enhancer-enhancer (E-E) interactions not well explored. In this work, we develop a novel deep learning approach, named Enhancer-enhancer contacts prediction (EnContact), to predict E-E contacts using genomic sequences as input. We statistically demonstrated the predicting ability of EnContact using training sets and testing sets derived from HiChIP data of seven cell lines. We also show that our model significantly outperforms other baseline methods. Besides, our model identifies finer-mapping E-E interactions from region-based chromatin contacts, where each region contains several enhancers. In addition, we identify a class of hub enhancers using the predicted E-E interactions and find that hub enhancers tend to be active across cell lines. We summarize that our EnContact model is capable of predicting E-E interactions using features automatically learned from genomic sequences.
| S-EPMC6746221 | biostudies-literature
Project description:BackgroundMicroRNAs (miRNAs) are a class of non-coding RNAs that play a pivotal role as gene expression regulators. These miRNAs are typically approximately 20 to 25 nucleotides long. The maturation of miRNAs requires Dicer cleavage at specific sites within the precursor miRNAs (pre-miRNAs). Recent advances in machine learning-based approaches for cleavage site prediction, such as PHDcleav and LBSizeCleav, have been reported. ReCGBM, a gradient boosting-based model, demonstrates superior performance compared with existing methods. Nonetheless, ReCGBM operates solely as a binary classifier despite the presence of two cleavage sites in a typical pre-miRNA. Previous approaches have focused on utilizing only a fraction of the structural information in pre-miRNAs, often overlooking comprehensive secondary structure information. There is a compelling need for the development of a novel model to address these limitations.ResultsIn this study, we developed a deep learning model for predicting the presence of a Dicer cleavage site within a pre-miRNA segment. This model was enhanced by an autoencoder that learned the secondary structure embeddings of pre-miRNA. Benchmarking experiments demonstrated that the performance of our model was comparable to that of ReCGBM in the binary classification tasks. In addition, our model excelled in multi-class classification tasks, making it a more versatile and practical solution than ReCGBM.ConclusionsOur proposed model exhibited superior performance compared with the current state-of-the-art model, underscoring the effectiveness of a deep learning approach in predicting Dicer cleavage sites. Furthermore, our model could be trained using only sequence and secondary structure information. Its capacity to accommodate multi-class classification tasks has enhanced the practical utility of our model.
| S-EPMC10775615 | biostudies-literature