ResearchComprehensive molecular profiling and high-performance computing have begun to transform biomedical research toward deeper integration of large, complex datasets. While massive data are routinely generated in research and clinical settings, analysis of such data are increasingly becoming the bottleneck in biomedical studies. The Computational Biology and Medicine Program (CBMP) at the Princess Margaret Cancer Centre develops innovative computational technologies to address scientific and clinical gaps, and optimize patient treatment. CBMP will work toward broadening access to complex cancer data and software tools, and promoting open science through increased transparency and reproducibility in biomedical research. Combining expertise in bioinformatics, epigenomics, proteomics, pharmacogenomics, biostatistics, machine learning, epidemiology and high-throughput molecular profiling, CBMP is uniquely positioned to advance cancer research through basic, translational and clinical approaches. CBMP will generate new comprehensive molecular datasets with deep phenotypes, implement novel analytical approaches, and drive multidisciplinary collaborations. Recognizing the complexity of translating research findings into real-world applications, CBMP will develop new assays and computational tools designed from the outset for broad use by the scientific community and health practitioners. This will maximize CBMP’s impact and return of investment.
Defining, Monitoring, and Adapting Cancer Management
Change the clinical conversation by making cancer measurable and actionable.The CBMP postulates that optimally selecting and matching quantifiable, often high dimensionality, cancer features (i.e., biomarkers) with appropriate therapeutic approaches will improve human cancer detection, treatment and monitoring, and ultimately improve both efficacy and toxicity outcomes. CBMP is taking a broad, multi-disciplinary approach to feature/biomarker selection, using diverse clinico-demographic, epidemiological, behavioural, imaging, pathologic, serologic and molecular (genomic, epigenomic, transcriptomic, proteomic) data. CBMP will develop adaptive tools to identify and link appropriate patterns of features to therapeutic management. As the sheer number of features are enormous, computational methods are ideal for feature reduction and selection. CBMP will also take a broad approach to defining therapeutic management: current active examples include cell-free approaches for early detection (CALIBRE), patient selection for de-escalating therapy or conversely prolonging therapy by modulating radiotherapy dose and field according to real-time tumor responses (MIRACLE), improving the precision of drug toxicity phenotyping for better therapeutic efficacy-toxicity ratios (DECLIP), and intelligent compound selection within large portfolios of novel compounds. One major action item will be to generate the evidence that will lead directly to clinical validation, testing in innovative feature-matched human trials, and eventual implementation into routine practice.
Linking Phenotypes to Molecular Signatures
Nominate new, data-driven questions that can be answered by clinical trials.The CBMP will work toward developing predictive computational models to understand interactions between genome, epigenome, transcriptome, proteome, and phenotype in human cancers. Our goal is to create models that accurately predict how molecular alterations in cancer including (i) germline and somatic genetic variants, (ii) gene regulatory changes, and (iii) proteome remodelling interact and impact cancer phenotypes. We will develop machine learning models of how a genomic/proteomic or experimental perturbation leads to a molecular phenotypic output, subsequently validated with targeted experiments and retrospective analysis of patient data. The CBMP will investigate the potential of preclinical cancer models for developing predictors of drug response. We propose to (i) aggregate the pharmacogenomic profiles of preclinical models (in vivo, ex vivo, and in vitro models) from the PM Living Biobank and public repositories, and (ii) develop novel computational pipelines for robust biomarker and target discovery and validation. Linking the preclinical biomarkers to clinical genomic profiles has the potential not only to match more patients to clinical trials based on the tumor genotypes, but also to increase the response rate by improving the quality of the genotype-matching.
Software and Data Engineering
Platformization of Everything: put information and tools in the hands of all users.Researchers often develop databases and scientific software that have a limited scope of application, are brittle and difficult to deploy in other environments, sometimes even within the same institution. Software engineers and data coordinators address this issue by designing highly modular, documented code and database structures following best programming practices using modern technology stacks. Recognizing the richness of the datasets and computational approaches developed internally, CBMP will promote these best practices and provide the expertise necessary for large-scale deployment and dissemination, consequently increasing the impact of PM research outputs. Doing so will not only overhaul the quality of the research enterprise within PM, but will also put us at the forefront of computational biology and medicine as the scientific community will increasingly rely on the high-quality data and software tools developed by PM. State-of-the-art software and data engineering is essential to ensure research reproducibility, a crucial aspect of open science. CBMP will work toward developing computational platforms that provide transparent, reproducible, and flexible analytical pipelines for large multimodal biomedical data. We will initially focus on the processing of molecular and pharmacological profiles of cancer samples through the use of automated processing pipelines and versioning to produce fully documented data objects for future analyses. We will extend the platform to other data types (e.g., patient health records, radiology and pathology imaging) and test its deployment on HPC4Health and Microsoft Azure.