Abstract 3972: Tumor accessiblity and composition play a major role on the efficiency of efflux transporter inhibitor - cytotoxic drug combination: Analysis with a mathematical model
Authors: Sostelly Alexandre , Payen Léa , Guitton Jérôme , Pietro Attilio Di , Falson Pierre , Boumendjel Ahcène , Freyer Gilles , Tod Michel 
Published: August 2012

Efflux transporters from the ABC family confer resistance to various anticancer drugs. Efflux transporter inhibitors were designed to reverse chemoresistance to cytotoxic drugs. Efficacy of such association is impacted by numerous factors in xenografted animals, such as tumor environment and biology. No study aims at quantifying the importance of these factors on the efficiency of association of cytotoxic-efflux transporter inhibitor. In-silico approach, through the development of mathematical models, allows testing the influence of such factors. This work aimed at evaluating the impact of tumor accessibility and composition, on efflux transporter inhibitors - cytotoxic combination with a mathematical model. Two studies (S1, S2) were carried out in mice xenografted with HEK293 cells overexpressing the ABCG2 transporter. Mice received irinotecan (CPT11) alone or combined to a new ABCG2 inhibitor, MBLI87. Tumor size was periodically measured during 4 weeks. Designs of both studies were similar but mice received a more intense dose of MBLI87 in S2 and delay of treatment onset was longer in S2. To model tumor growth, a multiscale model was developed including 4 submodels: - PK model of plasmatic drug disposition - Cellular interaction model of the cytotoxic drug accumulation in tumor in presence of inhibitor - Tumor growth model of the natural evolution of disease - Pharmacodynamic model of cytotoxic drug effect on tumor growth Cellular interaction model was based on in-vitro experiments and quantified the magnitude of CPT11 and its metabolite SN38 active efflux and the MBLI87 inhibition constant. A rate constant describing drug diffusion from plasma to tumor represented tumor accessibility. Three types of tumoral tissues were considered: proliferative, hypoxic and necrotic. Only proliferative tissues could grow and cytotoxic drugs could only affect proliferative cells. Model parameters were estimated with a non-linear mixed-effects approach using NONMEM software. Model was able to predict correctly tumor growth from our data. Addition of MBLI87 to CPT11 slowed the growth of tumors in S1 and S2. Our model showed that cytotoxic potency was equivalent in S1 and S2 but proportion of proliferative cells was smaller at treatment onset and drug active efflux was greater in S2. Equilibration between plasma and tumor was faster in S2 attesting better tumor accessibility owing to better vascularization. As a consequence, a different intensity in resistance reversion was found between S1 and S2: tumor size was 50% greater at day 40 in S2. This mathematical model quantified the role of tumor accessibility and composition on the efficiency of an efflux inhibitor - cytotoxic drug combination. It can be used as a simulation framework to optimize this type of interaction or as a template for early evaluation of other efflux transporter inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3972. doi:1538-7445.AM2012-3972