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.

SYNERGxDB: an integrative pharmacogenomic portal to identify synergistic drug combinations for precision oncology.

Drug-combination data portals have recently been introduced to mine huge amounts of pharmacological data with the aim of improving current chemotherapy strategies. However, these portals have only been investigated for isolated datasets, and molecular profiles of cancer cell lines are lacking. Here we developed a cloud-based pharmacogenomics portal called SYNERGxDB (http://SYNERGxDB.ca/) that integrates multiple high-throughput drug-combination studies with molecular and pharmacological profiles of a large panel of cancer cell lines. This portal enables the identification of synergistic drug combinations through harmonization and unified computational analysis. We integrated nine of the largest drug combination datasets from both academic groups and pharmaceutical companies, resulting in 22 507 unique drug combinations (1977 unique compounds) screened against 151 cancer cell lines. This data compendium includes metabolomics, gene expression, copy number and mutation profiles of the cancer cell lines. In addition, SYNERGxDB provides analytical tools to discover effective therapeutic combinations and predictive biomarkers across cancer, including specific types. Combining molecular and pharmacological profiles, we systematically explored the large space of univariate predictors of drug synergism. SYNERGxDB constitutes a comprehensive resource that opens new avenues of research for exploring the mechanism of action for drug synergy with the potential of identifying new treatment strategies for cancer patients.

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.

Effect of Radiation Therapy Quality Assurance on Nasopharyngeal Carcinoma: Usage of a Novel, Web-Based Quality Assurance Application.

PURPOSE: We used a new web application for rapid review of radiation therapy (RT) target volumes to evaluate the relationship between target delineation compliance with the international guidelines and outcomes of definitive RT for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: The data set consisted of computed tomography simulation scans, RT structures, and clinical data of 354 patients with pathology-confirmed NPC treated with intensity modulated RT between 2005 and 2017. Target volumes were peer-reviewed in RT quality assurance rounds, and target contours were revised, if recommended, before treatment. We imported the contours of intermediate-risk clinical target volumes of the primary tumor (CTVp) of 332 patients into the application. Inclusion of anatomic sites within intermediate-risk CTVp was determined in accordance with 2018 international guidelines for CTV delineation for NPC and correlated with time to local failure (TTLF) using Cox regression. RESULTS: In the peer-review quality assurance analysis, local and distant control and overall survival rates were similar between peer-reviewed and nonreviewed cases and between cases with and without target contour changes. In the CTV compliance analysis, with a median follow-up of 5.6 years, 5-year TTLF and overall survival rates were 93.1% and 85.9%, respectively. The most frequently non-guideline-compliant anatomic sites were sphenoid sinus (n = 69, 20.8%), followed by cavernous sinus (n = 38, 19.3%), left and right petrous apices (n = 37 and 32, 11.1% and 9.6%), and clivus (n = 14, 4.2%). Among 23 patients with a local failure (6.9%), the number of noncompliant cases was 8 for sphenoid sinus, 7 cavernous sinus, 4 left and 3 right petrous apices, and 2 clivus. Cavernous sinus-conforming cases showed higher TTLF in comparison with nonconforming cases (93.6% vs 89.1%, P = .013). Multivariable analysis confirmed that cavernous sinus noncompliance was prognostic for TTLF. CONCLUSIONS: Our application allowed rapid quantitative review of CTVp in a large NPC cohort. Although compliance with the international guidelines was high, undercoverage of the cavernous sinus was correlated with TTLF.

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.

Assessment of Genetic Drift in Large Pharmacogenomic Studies.

Genomic instability affects the reproducibility of experiments that rely on cancer cell lines. However, measuring the genomic integrity of these cells throughout a study is a costly endeavor that is commonly forgone. Here, we validate the identity of cancer cell lines in three pharmacogenomic studies and screen for genetic drift within and between datasets. Using SNP data from these datasets encompassing 1,497 unique cell lines and 63 unique pharmacological compounds, we show that genetic drift is widely prevalent in almost all cell lines with a median of 4.5%-6.1% of the total genome size drifted between any two isogenic cell lines. This study highlights the need for molecular profiling of cell lines to minimize the effects of passaging or misidentification in biomedical studies. We developed the CCLid web application, available at www.cclid.ca, to allow users to screen the genomic profiles of their cell lines against these datasets. A record of this paper's transparent peer review process is included in the Supplemental Information.