Agent-based models for prediction of tumor spheroid response to radiation and the hypoxia-activated prodrug SN30000 (Abstract #4523)

Abstract

Introduction: Hypoxia-activated prodrugs (HAPs) are a promising strategy to specifıcally target radioresistant hypoxic cells in tumors. We have used multicellular layers (MCLs) and steady state Green’s function pharmacokinetic/pharmacodynamic (PK/PD) modelling in microvascular networks to select SN30000 as a tirapazamine analogue with optimal spatial complementarity with radiation. However these models have several limitations such as lack of time dependent PK. Multicellular tumor spheroids are a more tractable model than MCLs for investigating PD parameters. However, the challenges of interpreting spheroid experiments in terms of spatial complementarity limits their application. We have developed an in silico agent-based (AB) tumor spheroid model, in which cell fate can be tracked as a function of time and is determined by spatially-varying concentrations of oxygen, glucose and therapeutic agents (radiation and HAP). The hypothesis is that our AB model can predict tumor spheroid response to radiation and SN30000, both alone and in combination. Methods: In the AB model, spheroid growth is simulated as a function of oxygen, glucose and drug concentrations determined by solving diffusion equations using oxygen consumption measured in HCT116 monolayers and glucose and SN30000 diffusion and metabolism measured in HCT116 MCLs and stirred cell suspensions, linked with intracellular reaction equations. Cell fate is determined by oxygen, glucose and drug concentrations. Spheroid diameter, cell survival and hypoxic fraction of HCT116 spheroids grown at a range of oxygen and initial glucose concentrations were compared to model predictions, as was glucose depletion from the culture medium. Radiation (cobalt-60) and SN30000 induced clonogenic cell killing under oxia and anoxia was determined using HCT116 monolayers. Model simulations of HCT116 spheroid response to radiation and SN30000 were compared to experimental results. Results: The model reproduced known features of spheroids including oxygen and glucose gradients, rapid cell proliferation at the periphery and central hypoxia and necrosis. Measured HCT116 spheroid diameters increased linearly with time, at rates that decreased at lower ambient O2 concentrations. Spheroid growth and glucose depletion was well-fıtted by the AB model. Good agreement was found between simulated and measured clonogenic cell killing by radiation and SN30000, while the model underestimated spheroid growth delay by radiation and SN30000 than experimental observation. Discussion: An oxygen and glucose dependent AB model for growth and PD response (cell killing and growth delay) of HCT116 spheroids has been developed and calibrated using experimentally determined parameters. Further development of this model will link cell fates (including cell cycle arrest) explicitly to DNA damage responses and O2 and glucose-dependence of cell proliferation and survival.