Abstract 182: Bridging gaps in translational biology: Exploring pharmacokinetic/pharmacodynamic/efficacy relationships and combination treatments in 3D tumor models using a microphysiological system
Authors: Petreus Tudor , Kostrzewski Tomasz , Singh Dharaminder , Hughes David 
Published: June 2022

Abstract
Accurate profiling of pharmacokinetic (PK) and pharmacodynamic (PD) parameters is critical in the discovery and development of new oncology drugs, schedules and combinations. Predicting these parameters pre-clinically is essential to determine efficacious doses required in clinical treatment. The PK/PD/efficacy relationship has traditionally been characterized in xenograft models, owing to an absence of viable in vitro alternatives. However, murine/human PK parameters can vary for many compounds. To explore PK/PD/efficiency relationships on 3D tumor models and organoids, we have developed a microphysiological system (MPS) able to mimic or reverse translate clinical/in vivo drug exposure (PK) profiles on an in vitro system. The MPS can deliver up to two different drugs to tumor models in monotherapy or combinations, using customizable PK profiles and treatment schedules, by stepwise addition and removal of cell culture medium in a regular 24-well plate format. We first recapitulated the in vivo PK/PD relationship for a PI3K inhibitor (BYL719- t1/2 6 hours, equivalent to 50 mg/kg murine oral dose), used to treat an A549 non-small cell lung carcinoma model. Following BYL719 exposure in the MPS device cellular p-AKT levels (biomarker of PI3K pathway activity) fell by up to 90%, but then recovered to pre-dosed levels over a 24-hour period as drug concentrations in the tumor reduce, as observed in vivo. This effect lacks in standard in vitro bolus experiments. Next, we explored whether the MPS could recapitulate in vivo effects of combining topoisomerase inhibitors with DNA-damage-response inhibitors (DDRi) in the treatment of colorectal tumors. Being almost non-toxic to normal cells, DDRi’s enhance DNA damage induced by topoisomerase inhibitors. 3D colorectal tumor models were treated by the MPS device for six days with monotherapy or combination therapy of the two compounds (SN38 Cmax = 20 nM, DDRi Cmax = 162 nM), recapitulating their in vivo PK profiles. Viability assays showed the benefits of combination therapy (viability 48.5% vs controls) over topoisomerase inhibitor monotherapy (viability 58.3% compared vs controls), with efficacy rates consistent with in vivo observations, rather than static 2D in vitro cultures which were over predictive. Overall, our MPS is able to accurately capture PK/PD/efficacy relationships using in vitro cultures. This approach will enable a greater understanding of drug properties and optimal treatment regimens to ultimately enable better design of clinical studies.
Citation Format: Tudor Petreus, Tomasz Kostrzewski, Dharaminder Singh, David Hughes. Bridging gaps in translational biology: Exploring pharmacokinetic/pharmacodynamic/efficacy relationships and combination treatments in 3D tumor models using a microphysiological system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 182.