Machine Learning for Cancer Drug Combination.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang Z
PROVIDER: S-EPMC8141105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Drug combination is now a hot research topic in the pharmaceutical industry, but experiment-based methodologies are extremely costly in time and money. Many computational methods have been proposed to address these problems by starting from existing drug combinations. However, in most cases, only molecular structure information is included, which covers too limited a set of drug characteristics to efficiently screen drug combinations. Here, we integrated similarity-based multifeature drug data to improve the prediction accuracy by using the neighbor recommender method combined with ensemble learning algorithms. By conducting feature assessment analysis, we selected the most useful drug features and achieved 0.964 AUC in the ensemble models. The comparison results showed that the ensemble models outperform traditional machine learning algorithms such as support vector machine (SVM), naïve Bayes (NB), and logistic regression (GLM). Furthermore, we predicted 7 candidate drug combinations for a specific drug, paclitaxel, and successfully verified that the two of the predicted combinations have promising effects.
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Project description:Combination therapy has shown an obvious efficacy on complex diseases and can greatly reduce the development of drug resistance. However, even with high-throughput screens, experimental methods are insufficient to explore novel drug combinations. In order to reduce the search space of drug combinations, there is an urgent need to develop more efficient computational methods to predict novel drug combinations. In recent decades, more and more machine learning (ML) algorithms have been applied to improve the predictive performance. The object of this study is to introduce and discuss the recent applications of ML methods and the widely used databases in drug combination prediction. In this study, we first describe the concept and controversy of synergism between drug combinations. Then, we investigate various publicly available data resources and tools for prediction tasks. Next, ML methods including classic ML and deep learning methods applied in drug combination prediction are introduced. Finally, we summarize the challenges to ML methods in prediction tasks and provide a discussion on future work.
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Project description:Gene expression profiles were generated from 199 primary breast cancer patients. Samples 1-176 were used in another study, GEO Series GSE22820, and form the training data set in this study. Sample numbers 200-222 form a validation set. This data is used to model a machine learning classifier for Estrogen Receptor Status. RNA was isolated from 199 primary breast cancer patients. A machine learning classifier was built to predict ER status using only three gene features.
2013-01-01 | E-GEOD-29210 | biostudies-arrayexpress
Project description:Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. In this study, we profile 80 FDA-approved and clinically tested drugs in neural cell cultures, with the goal of producing a ranked list of possible repurposing candidates.
2021-01-14 | GSE164788 | GEO
Project description:BackgroundThe mechanism of action for most cancer drugs is not clear. Large-scale pharmacogenomic cancer cell line datasets offer a rich resource to obtain this knowledge. Here, we present an analysis strategy for revealing biological pathways that contribute to drug response using publicly available pharmacogenomic cancer cell line datasets.MethodsWe present a custom machine-learning based approach for identifying biological pathways involved in cancer drug response. We test the utility of our approach with a pan-cancer analysis of ML210, an inhibitor of GPX4, and a melanoma-focused analysis of inhibitors of BRAFV600. We apply our approach to reveal determinants of drug resistance to microtubule inhibitors.ResultsOur method implicated lipid metabolism and Rac1/cytoskeleton signaling in the context of ML210 and BRAF inhibitor response, respectively. These findings are consistent with current knowledge of how these drugs work. For microtubule inhibitors, our approach implicated Notch and Akt signaling as pathways that associated with response.ConclusionsOur results demonstrate the utility of combining informed feature selection and machine learning algorithms in understanding cancer drug response.
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Project description:Motivation:Timely identification of Mycobacterium tuberculosis (MTB) resistance to existing drugs is vital to decrease mortality and prevent the amplification of existing antibiotic resistance. Machine learning methods have been widely applied for timely predicting resistance of MTB given a specific drug and identifying resistance markers. However, they have been not validated on a large cohort of MTB samples from multi-centers across the world in terms of resistance prediction and resistance marker identification. Summary:Several machine learning classifiers and linear dimension reduction techniques were developed and compared for a cohort of 13402 isolates collected from 16 countries across six continents and tested 11 drugs. Results:Compared to conventional molecular diagnostic test, area under curve (AUC) of the best machine learning classifier increased for all drugs especially by 23.11%, 15.22%, and 10.14% for pyrazinamide (PZA), ciprofloxacin (CIP), and ofloxacin (OFX) respectively (p < 0.01). Logistic regression (LR) and gradient tree boosting (GBT) found to perform better than other techniques. Moreover, LR/GBT with a sparse principal component analysis/non-negative matrix factorisation step compared with the classifier alone enhanced the best performance in terms of F1-score by 12.54%, 4.61%, 7.45%, and 9.58% for amikacin (AK), moxifloxacin (MOX), OFX, and capreomycin (CAP) respectively, as well increasing AUC for AK and CAP. Results provided a comprehensive comparison of various techniques and confirmed the application of machine learning for better prediction of the large diverse TB data. Furthermore, mutation ranking showed the possibility of finding new resistance/susceptible markers. Availability:The source code can be found at http://www.robots.ox.ac.uk/~davidc/code.php. Supplementary information:Supplementary data are available at Bioinformatics online.
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Project description:Chemotherapy resistance is a major challenge to the effective treatment of cancer. Thus, a systematic pipeline for the efficient identification of effective combination treatments could bring huge biomedical benefit. In order to facilitate rational design of combination therapies, we developed a comprehensive computational model that incorporates the available biological knowledge and relevant experimental data on the life-and-death response of individual cancer cells to cisplatin or cisplatin combined with the TNF-related apoptosis-inducing ligand (TRAIL). The model's predictions, that a combination treatment of cisplatin and TRAIL would enhance cancer cell death and exhibit a "two-wave killing" temporal pattern, was validated by measuring the dynamics of p53 accumulation, cell fate, and cell death in single cells. The validated model was then subjected to a systematic analysis with an ensemble of diverse machine learning methods. Though each method is characterized by a different algorithm, they collectively identified several molecular players that can sensitize tumor cells to cisplatin-induced apoptosis (sensitizers). The identified sensitizers are consistent with previous experimental observations. Overall, we have illustrated that machine learning analysis of an experimentally validated mechanistic model can convert our available knowledge into the identity of biologically meaningful sensitizers. This knowledge can then be leveraged to design treatment strategies that could improve the efficacy of chemotherapy.
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Project description:Understanding drug-drug interactions is an essential step to reduce the risk of adverse drug events before clinical drug co-prescription. Existing methods, commonly integrating heterogeneous data to increase model performance, often suffer from a high model complexity, As such, how to elucidate the molecular mechanisms underlying drug-drug interactions while preserving rational biological interpretability is a challenging task in computational modeling for drug discovery. In this study, we attempt to investigate drug-drug interactions via the associations between genes that two drugs target. For this purpose, we propose a simple f drug target profile representation to depict drugs and drug pairs, from which an l2-regularized logistic regression model is built to predict drug-drug interactions. Furthermore, we define several statistical metrics in the context of human protein-protein interaction networks and signaling pathways to measure the interaction intensity, interaction efficacy and action range between two drugs. Large-scale empirical studies including both cross validation and independent test show that the proposed drug target profiles-based machine learning framework outperforms existing data integration-based methods. The proposed statistical metrics show that two drugs easily interact in the cases that they target common genes; or their target genes connect via short paths in protein-protein interaction networks; or their target genes are located at signaling pathways that have cross-talks. The unravelled mechanisms could provide biological insights into potential adverse drug reactions of co-prescribed drugs.
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Project description:The prevalence of infections by nontuberculous mycobacteria is increasing, having surpassed tuberculosis in the United States and much of the developed world. Nontuberculous mycobacteria occur naturally in the environment and are a significant problem for patients with underlying lung diseases such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Current treatment regimens are lengthy, complicated, toxic and they are often unsuccessful as seen by disease recurrence. Mycobacterium abscessus is one of the most commonly encountered organisms in nontuberculous mycobacteria disease and it is the most difficult to eradicate. There is currently no systematically proven regimen that is effective for treating M. abscessus infections. Our approach to drug discovery integrates machine learning, medicinal chemistry and in vitro testing and has been previously applied to Mycobacterium tuberculosis. We have now identified several novel 1-(phenylsulfonyl)-1H-benzimidazol-2-amines that have weak activity on M. abscessus in vitro but may represent a starting point for future further medicinal chemistry optimization. We also address limitations still to be overcome with the machine learning approach for M. abscessus.
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