Abstract B49: The interplay between hypoxia-activated drugs and the microenvironment in pancreatic cancers: a computational study
Authors: Rejniak Katarzyna A. , Kim MunJu , Wojtkowiak Jonathan , Gillies Robert J. 
Published: August 2014

Pancreatic cancers contain significant amounts of stromal tissue that contributes to poor penetration of both metabolites and drug particles. As a result these tumors are hypoxic and standard therapeutic compounds show much lower efficacy in vivo then in laboratory experiments. To test optimal administration schedules of a novel class of drugs that are activated in the tumor hypoxic regions (HAPs, hypoxia-activated pro-drugs), as well as strategies to make the tumors more sensitive to these drugs, we developed a mechanistic computational model carefully parameterized with experimental data. This interdisciplinary approach has been used to investigate complex interplay between HAPs and tumor microenvironmental heterogeneity.

Our in silico methods include a protocol for model parameterization with explicitly defined tissue morphology based on histology of mice xenograft tumors; here we used a pancreatic cancer cell line MiaPaCa. We designed algorithms for model calibration with oxygen-related quantitative experimental data, such as cell oxygen consumption profiles, oxygen diffusion measurements and the extent of tissue hypoxia. We performed a simulation study in which drug-related parameters were systematically varied over a wide range of values in order to determine which HAPs' pharmacokinetic properties are the most significant in drug penetration into the tumor tissue.

Our computational results showed that heterogeneity in tissue composition, such as irregular spatial configuration of tumor cells, might solely be responsible for the emergence of tissue zones that are not exposed to drugs in concentrations sufficient to provide therapeutic action. We demonstrated that complex interactions between the dynamics of HAPs and tumor microenvironment may lead to the shift of tissue metabolic profile, and the emergence of tissue zones in which tumor cells are only partially exposed to the activated drug leading to the emergence of resistant cell subpopulations. We suggested combinations of physical properties of both inactive and activated drug molecules (diffusive coefficients, transition levels and activation ranges) that are advantageous for achieving deep drug penetration. We also simulated different orders and timings of administration of HAPs and their sensitizers to find out an optimal schedule resulting in high drug efficacy.

In conclusion, we will present a current state of the computational model integrated with experimental data and calibrated to pancreatic tumor xenografts that aim on providing an analytical tool in designing drug properties and drug administration schedules that will optimize drug penetration into the tumor tissue and enhance their therapeutic efficacy.

Citation Format: Katarzyna A. Rejniak, MunJu Kim, Jonathan Wojtkowiak, Robert J. Gillies. The interplay between hypoxia-activated drugs and the microenvironment in pancreatic cancers: a computational study. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B49.