Abstract A33: An individualized predictive 3D model of tumor response to topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma

Abstract

Abstract Resistance to chemotherapeutics and targeted therapies in pediatric solid tumors including neuroblastoma is a common cause of poor clinical outcome. These failures in part stem from shortcomings in understanding inter- and intra-tumor heterogeneities of drug penetration due to heterogeneities in blood perfusion. Herein we present an individualized predictive three-dimensional (3D) model of tumor response to topotecan (TPT) for a patient-derived orthotopic xenograft model of pediatric NB5 neuroblastoma. This model is integrated with an individualized physiologically-based pharmacokinetic (PBPK) model of TPT and accounts for the effects of inter- and intra-tumor heterogeneities in blood perfusion on tumor response. This model uses a set of 3D reaction-diffusion equations to simulate transport of TPT from blood vessels into the tumor tissue and its flux in and out of intracellular space. The transport model takes inputs from three spatial scales (systemic, tissue and cells) to predict TPT exposure maps defined over the volume of an individual tumor: a) plasma concentration-time profiles from an individualized physiologically-based pharmacokinetic (PBPK) model of TPT, b) 3D blood perfusion map of the individual tumor from contrast enhanced ultrasound (CEUS) using VEVO 2100 imaging system, and c) in vitro TPT cellular uptake and efflux kinetics from two-photon imaging. The transport model also gives feedback to the PBPK model. We use in vitro pharmacodynamics (PD) experiments with NB5 cells exposed to TPT to derive probabilistic PD-rules for drug effects (γ-H2AX response). Based on these rules and exposure maps predicted by the transport model, we then compute probabilities of effects for the entire tumor volume. We validate the predicted drug effect maps by comparing them to observed effect data (from three dosage levels) measured by immunohistochemistry marker for γ-H2AX from the same tumor (location matched serial sections) using spatial correlation techniques. Citation Format: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Jessica Roberts, Clinton F. Stewart, András Sablauer. An individualized predictive 3D model of tumor response to topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A33.