Protocol for stratification of triple-negative breast cancer patients using in silico signaling dynamics.

Personalized kinetic models can predict potential biomarkers and drug targets. Here, we provide a step-by-step approach for building an executable mathematical model from text and integrating transcriptomic datasets. We additionally describe the steps to personalize the mechanistic model and to stratify patients with triple-negative breast cancer (TNBC) based on in silico signaling dynamics. This protocol can also be applied to any signaling pathway for patient-specific modeling. For complete details on the use and execution of this protocol, please refer to Imoto et al. (2022).

A text-based computational framework for patient -specific modeling for classification of cancers.

Patient heterogeneity precludes cancer treatment and drug development; hence, development of methods for finding prognostic markers for individual treatment is urgently required. Here, we present Pasmopy (Patient-Specific Modeling in Python), a computational framework for stratification of patients using in silico signaling dynamics. Pasmopy converts texts and sentences on biochemical systems into an executable mathematical model. Using this framework, we built a model of the ErbB receptor signaling network, trained in cultured cell lines, and performed in silico simulation of 377 patients with breast cancer using The Cancer Genome Atlas (TCGA) transcriptome datasets. The temporal dynamics of Akt, extracellular signal-regulated kinase (ERK), and c-Myc in each patient were able to accurately predict the difference in prognosis and sensitivity to kinase inhibitors in triple-negative breast cancer (TNBC). Our model applies to any type of signaling network and facilitates the network-based use of prognostic markers and prediction of drug response.

Building patient-specific models for receptor tyrosine kinase signaling networks.

Cancer progresses due to changes in the dynamic interactions of multidimensional factors associated with gene mutations. Cancer research has actively adopted computational methods, including data-driven and mathematical model-driven approaches, to identify causative factors and regulatory rules that can explain the complexity and diversity of cancers. A data-driven, statistics-based approach revealed correlations between gene alterations and clinical outcomes in many types of cancers. A model-driven mathematical approach has elucidated the dynamic features of cancer networks and identified the mechanisms of drug efficacy and resistance. More recently, machine learning methods have emerged that can be used for mining omics data and classifying patient. However, as the strengths and weaknesses of each method becoming apparent, new analytical tools are emerging to combine and improve the methodologies and maximize their predictive power for classifying cancer subtypes and prognosis. Here, we introduce recent advances in cancer systems biology aimed at personalized medicine, with focus on the receptor tyrosine kinase signaling network.