A virtual B cell lymphoma model to predict effective combination therapy

Abstract

AbstractThe complexity of cancer signaling networks limits the efficacy of most single agent treatments and brings about challenges in identifying effective combinatorial therapies. Using chronic active B cell receptor (BCR) signaling in diffuse large B cell lymphoma (DLBCL) as a model system, we established a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex crosstalk between the NF{kappa}B, ERK and AKT pathways; and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model we predicted viability responses of many single drug and drug combinations that are in agreement with experimental data. Under this framework, we exhaustively predicted and ranked the efficacy and synergism of all possible combinatorial inhibitions of eleven currently targetable kinases in the BCR signaling network. Our work established a detailed kinetic model of the core BCR signaling network and provides the means to explore the large space of possible drug combinations.\n\nAuthor SummaryUsing chronic active B cell receptor (BCR) signaling in diffuse large B cell lymphoma(DLBCL) as a model system, we developed a kinetic-modeling based computational framework for predicting effective combination therapy in silico. By integrative modeling of signal transduction, drug kinetics and tumor growth, we were able to directly predict drug-induced cell viability response at various dosages, which were in agreement with published cell line experimental data. We implemented computational screening methods that identified potent and synergistic combinations in silico and validated our independent predictions in vitro.