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

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.

Assessing therapy response in patient-derived xenografts.

Quantifying response to drug treatment in mouse models of human cancer is important for treatment development and assignment, yet remains a challenging task. To be able to translate the results of the experiments more readily, a preferred measure to quantify this response should take into account more of the available experimental data, including both tumor size over time and the variation among replicates. We propose a theoretically grounded measure, KuLGaP, to compute the difference between the treatment and control arms. We test and compare KuLGaP to four widely used response measures using 329 patient-derived xenograft (PDX) models. Our results show that KuLGaP is more selective than currently existing measures, reduces the risk of false-positive calls, and improves translation of the laboratory results to clinical practice. We also show that outcomes of human treatment better align with the results of the KuLGaP measure than other response measures. KuLGaP has the potential to become a measure of choice for quantifying drug treatment in mouse models as it can be easily used via the kulgap.ca website.

Orchestrating and sharing large multimodal data for transparent and reproducible research.

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.

Pathway-Based Drug Response Prediction Using Similarity Identification in Gene Expression.

Lapatinib and trastuzumab (Herceptin) are targeted therapies designed for patients with HER2+ breast tumors. Although these therapies improved survival rates of patients with this tumor type, not all the patients harboring HER2 amplification respond to these drugs. The NeoALTTO clinical trial was designed to test whether a higher response rate can be achieved by combining lapatinib and trastuzumab. Although the combination therapy showed almost double the response rate compared to the monotherapies, 40% of the patients did not respond to the treatment. In this study, we sought to identify biomarkers of HER2+ breast cancer patients' response to drugs relying on gene expression profiles of tumors. We show that univariate gene expression-based biomarkers are significant but weak predictors of drug response. We further show that pathway activities, estimated from gene expression patterns quantified using the recent transcriptional similarity coefficient (TSC) between the tumor samples, yield high predictive value for therapy response (concordance index >0.8, p < 0.05). Moreover, machine learning models, built using multiple algorithms including logistic regression, naive Bayes, random forest, k-nearest neighbor, and support vector machine, for predicting drug response in the NeoALTTO clinical trial, resulted in lower performance compared to our pathway-based approach. Our results indicate that transcriptional similarity of biological pathways can be used to predict lapatinib and trastuzumab response in HER2+ breast cancer.

ToxicoDB: an integrated database to mine and visualize large-scale toxicogenomic datasets.

In the past few decades, major initiatives have been launched around the world to address chemical safety testing. These efforts aim to innovate and improve the efficacy of existing methods with the long-term goal of developing new risk assessment paradigms. The transcriptomic and toxicological profiling of mammalian cells has resulted in the creation of multiple toxicogenomic datasets and corresponding tools for analysis. To enable easy access and analysis of these valuable toxicogenomic data, we have developed ToxicoDB (toxicodb.ca), a free and open cloud-based platform integrating data from large in vitro toxicogenomic studies, including gene expression profiles of primary human and rat hepatocytes treated with 231 potential toxicants. To efficiently mine these complex toxicogenomic data, ToxicoDB provides users with harmonized chemical annotations, time- and dose-dependent plots of compounds across datasets, as well as the toxicity-related pathway analysis. The data in ToxicoDB have been generated using our open-source R package, ToxicoGx (github.com/bhklab/ToxicoGx). Altogether, ToxicoDB provides a streamlined process for mining highly organized, curated, and accessible toxicogenomic data that can be ultimately applied to preclinical toxicity studies and further our understanding of adverse outcomes.