Ewa Kizling

Bio: Ewa Kizling is an academic researcher from University of Warsaw. The author has contributed to research in topics: Gene & Druggability. The author has an hindex of 1, co-authored 2 publications receiving 1 citations.

Interpretable deep recommender system model for prediction of kinase inhibitor efficacy across cancer cell lines.

Abstract: Computational models for drug sensitivity prediction have the potential to significantly improve personalized cancer medicine. Drug sensitivity assays, combined with profiling of cancer cell lines and drugs become increasingly available for training such models. Multiple methods were proposed for predicting drug sensitivity from cancer cell line features, some in a multi-task fashion. So far, no such model leveraged drug inhibition profiles. Importantly, multi-task models require a tailored approach to model interpretability. In this work, we develop DEERS, a neural network recommender system for kinase inhibitor sensitivity prediction. The model utilizes molecular features of the cancer cell lines and kinase inhibition profiles of the drugs. DEERS incorporates two autoencoders to project cell line and drug features into 10-dimensional hidden representations and a feed-forward neural network to combine them into response prediction. We propose a novel interpretability approach, which in addition to the set of modeled features considers also the genes and processes outside of this set. Our approach outperforms simpler matrix factorization models, achieving R $$=$$ 0.82 correlation between true and predicted response for the unseen cell lines. The interpretability analysis identifies 67 biological processes that drive the cell line sensitivity to particular compounds. Detailed case studies are shown for PHA-793887, XMD14-99 and Dabrafenib.

Interpretable deep recommender system model for prediction of kinase inhibitor efficacy across cancer cell lines

Abstract: Computational models for drug sensitivity prediction have the potential to revolutionise personalized cancer medicine. Drug sensitivity assays, as well as profiling of cancer cell lines and drugs becomes increasingly available for training such models. Machine learning methods for drug sensitivity prediction must be optimized for: (i) leveraging the wealth of information about both cancer cell lines and drugs, (ii) predictive performance and (iii) interpretability. Multiple methods were proposed for predicting drug sensitivity from cancer cell line features, some in a multi-task fashion. So far, no such model leveraged drug inhibition profiles. Recent neural network-based recommender systems arise as models capable of predicting cancer cell line response to drugs from their biological features with high prediction accuracy. These models, however, require a tailored approach to model interpretability. In this work, we develop a neural network recommender system for kinase inhibitor sensitivity prediction called DEERS. The model utilizes molecular features of the cancer cell lines and kinase inhibition profiles of the drugs. DEERS incorporates two autoencoders to project cell line and drug features into 10-dimensional hidden representations and a feed-forward neural network to combine them into response prediction. We propose a novel model interpretability approach offering the widest possible assessment of the specific genes and biological processes that underlie the action of the drugs on the cell lines. The approach considers also such genes and processes that were not included in the set of modeled features. Our approach outperforms simpler matrix factorization models, achieving R=0.82 correlation between true and predicted response for the unseen cell lines. Using the interpretability analysis, we evaluate correlation of all human genes with each of the hidden cell line dimensions. Subsequently, we identify 67 biological processes associated with these dimensions. Combined with drug response data, these associations point at the processes that drive the cell line sensitivity to particular compounds. Detailed case studies are shown for PHA-793887, XMD14-99 and Dabrafenib. Our framework provides an expressive, multitask neural network model with a custom interpretability approach for inferring underlying biological factors and explaining cancer cell response to drugs.

SLIDE-VIP: a comprehensive, cell line- and patient-based framework for synthetic lethality prediction in DNA damage repair, chromatin remodeling and cell cycle

Abstract: Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing cancer therapies. However, identification of SL interactions is challenging, due to a large number of possible gene pairs, inherent noise and confounding factors in the observed signal. To discover robust SL interactions, we devised SLIDE-VIP, a novel framework combining eight statistical tests, including a new patient data-based test iSurvLRT. SLIDE-VIP leverages multi-omics data from four different sources: gene inactivation cell line screens, cancer patient data, drug screens and gene pathways. We applied SLIDE-VIP to discover SL interactions between genes involved in DNA damage repair, chromatin remodeling and cell cycle, and their potentially druggable partners. The top 883 ranking SL candidates had strong evidence in cell line and patient data, 250-fold reducing the initial space of 200K pairs. Drug screen and pathway tests provided additional corroboration and insights into these interactions. We rediscovered well-known SL pairs such as RB1 and E2F3 or PRKDC and ATM, and in addition, proposed strong novel SL candidates such as PTEN and PIK3CB. In summary, SLIDE-VIP opens the door to the discovery of SL interactions with clinical potential. All analysis and visualizations are available via the online SLIDE-VIP WebApp.

Synthetic lethality prediction in DNA damage repair, chromatin remodeling and the cell cycle using multi-omics data from cell lines and patients.

Abstract: Abstract Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing cancer therapies. However, identification of SL interactions is challenging, due to a large number of possible gene pairs, inherent noise and confounding factors in the observed signal. To discover robust SL interactions, we devised SLIDE-VIP, a novel framework combining eight statistical tests, including a new patient data-based test iSurvLRT. SLIDE-VIP leverages multi-omics data from four different sources: gene inactivation cell line screens, cancer patient data, drug screens and gene pathways. We applied SLIDE-VIP to discover SL interactions between genes involved in DNA damage repair, chromatin remodeling and cell cycle, and their potentially druggable partners. The top 883 ranking SL candidates had strong evidence in cell line and patient data, 250-fold reducing the initial space of 200K pairs. Drug screen and pathway tests provided additional corroboration and insights into these interactions. We rediscovered well-known SL pairs such as RB1 and E2F3 or PRKDC and ATM, and in addition, proposed strong novel SL candidates such as PTEN and PIK3CB. In summary, SLIDE-VIP opens the door to the discovery of SL interactions with clinical potential. All analysis and visualizations are available via the online SLIDE-VIP WebApp.

PharmacoDB 2.0: improving scalability and transparency of in vitro pharmacogenomics analysis.

Abstract: Cancer pharmacogenomics studies provide valuable insights into disease progression and associations between genomic features and drug response. PharmacoDB integrates multiple cancer pharmacogenomics datasets profiling approved and investigational drugs across cell lines from diverse tissue types. The web-application enables users to efficiently navigate across datasets, view and compare drug dose-response data for a specific drug-cell line pair. In the new version of PharmacoDB (version 2.0, https://pharmacodb.ca/), we present (i) new datasets such as NCI-60, the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) dataset, as well as updated data from the Genomics of Drug Sensitivity in Cancer (GDSC) and the Genentech Cell Line Screening Initiative (gCSI); (ii) implementation of FAIR data pipelines using ORCESTRA and PharmacoDI; (iii) enhancements to drug-response analysis such as tissue distribution of dose-response metrics and biomarker analysis; and (iv) improved connectivity to drug and cell line databases in the community. The web interface has been rewritten using a modern technology stack to ensure scalability and standardization to accommodate growing pharmacogenomics datasets. PharmacoDB 2.0 is a valuable tool for mining pharmacogenomics datasets, comparing and assessing drug-response phenotypes of cancer models.

Deep learning methods for drug response prediction in cancer: Predominant and emerging trends

Abstract: Cancer claims millions of lives yearly worldwide. While many therapies have been made available in recent years, by in large cancer remains unsolved. Exploiting computational predictive models to study and treat cancer holds great promise in improving drug development and personalized design of treatment plans, ultimately suppressing tumors, alleviating suffering, and prolonging lives of patients. A wave of recent papers demonstrates promising results in predicting cancer response to drug treatments while utilizing deep learning methods. These papers investigate diverse data representations, neural network architectures, learning methodologies, and evaluations schemes. However, deciphering promising predominant and emerging trends is difficult due to the variety of explored methods and lack of standardized framework for comparing drug response prediction models. To obtain a comprehensive landscape of deep learning methods, we conducted an extensive search and analysis of deep learning models that predict the response to single drug treatments. A total of 61 deep learning-based models have been curated, and summary plots were generated. Based on the analysis, observable patterns and prevalence of methods have been revealed. This review allows to better understand the current state of the field and identify major challenges and promising solution paths.

Opportunities and challenges in interpretable deep learning for drug sensitivity prediction of cancer cells

Abstract: In precision oncology, therapy stratification is done based on the patients’ tumor molecular profile. Modeling and prediction of the drug response for a given tumor molecular type will further improve therapeutic decision-making for cancer patients. Indeed, deep learning methods hold great potential for drug sensitivity prediction, but a major problem is that these models are black box algorithms and do not clarify the mechanisms of action. This puts a limitation on their clinical implementation. To address this concern, many recent studies attempt to overcome these issues by developing interpretable deep learning methods that facilitate the understanding of the logic behind the drug response prediction. In this review, we discuss strengths and limitations of recent approaches, and suggest future directions that could guide further improvement of interpretable deep learning in drug sensitivity prediction in cancer research.

Improved drug response prediction by drug target data integration via network-based profiling

Abstract: Drug response prediction (DRP) is important for precision medicine to predict how a patient would react to a drug before administration. Existing studies take the cell line transcriptome data, and the chemical structure of drugs as input and predict drug response as IC50 or AUC values. Intuitively, use of drug target interaction (DTI) information can be useful for DRP. However, use of DTI is difficult because existing drug response database such as CCLE and GDSC do not have information about transcriptome after drug treatment. Although transcriptome after drug treatment is not available, if we can compute the perturbation effects by the pharmacologic modulation of target gene, we can utilize the DTI information in CCLE and GDSC. In this study, we proposed a framework that can improve existing deep learning-based DRP models by effectively utilizing drug target information. Our framework includes NetGP, a module to compute gene perturbation scores by the network propagation technique on a network. NetGP produces genes in a ranked list in terms of gene perturbation scores and the ranked genes are input to a multi-layer perceptron to generate a fixed dimension vector for the integration with existing DRP models. This integration is done in a model-agnostic way so that any existing DRP tool can be incorporated. As a result, our framework boosts the performance of existing DRP models, in 64 of 72 comparisons. The performance gains are larger especially for test scenarios with samples with unseen drugs by large margins up to 34% in Pearson's correlation coefficient.