Probabilistic Boolean Modeling of Pre-clinical Tumor Models for Biomarker Identification in Cancer Drug Development

As high-throughput sequencing experiments become more widely used in pre-clinical and clinical settings, pharmacogenetic and pharmacogenomic biomarker development plays an increasingly important role in oncology drug development pipelines and programs. Consequently, computer-based learning approaches have entered into use at multiple stages in pre-clinical and clinical pipelines. However, few approaches are available to identify interpretable and implementable biomarkers of response early in the drug development process when only small pre-clinical data packages are available. To address the need for early-stage biomarker development using pre-clinical tumor models, we have adapted the previously published Probabilistic Target Inhibitor Map (PTIM) platform to the challenge of biomarker hypothesis development, and denoted this approach the Probabilistic Target Map-Biomarker (PTM-Biomarker). In this article, we detail the history and design philosophy of PTM-Biomarker, and present two case studies using the biomarker discovery tool to illustrate its utility in guiding cancer drug development. © 2021 Wiley Periodicals LLC.