Frances Brightman, Eric Fernandez, David Orrell, David Fell, Christophe Chassagnole
Physiomics plc
Objectives: Synergistic combinations of standard-of-care drugs or new chemical or biological entities show much promise in the treatment of cancer, and there is a great deal of interest in this strategy. However, the increasing number of possible combinations makes the task of selecting the best regimens particularly difficult. Although xenografts represent a convenient and relatively inexpensive approach to assessing the likely efficacy of proposed dosing regimens in vivo, the number of permutations that can be tested is still limited by practical considerations. We have therefore explored the use of three-dimensional tumor cell cultures (microtissues) as a more cost-effective alternative to xenografts for validating Virtual Tumor™ predictions.
Methods: We have developed a computerized PK-PD model of a growing tumor, called the Virtual Tumor™. We previously demonstrated that this platform can successfully simulate the outcome of various drug combination schedules in xenografts, as well as predict optimal drug schedules and combinations. In particular, we predicted that the efficacy of a gemcitabine-docetaxel combination could vary greatly depending on the scheduling of the drug administration, and verified these findings in vivo in the MX-1 xenograft mouse model. We have now conducted a comparable study using MX-1 microtissues, in which the cultures were treated with these same two drugs in isolation or in combination, according to various regimens.
Results: Here we show how the microtissue Virtual Tumor™ model can be employed to simulate microtissue growth and response to drug treatment, and the capability of this model to predict drug synergy.
Conclusions: We discuss the potential for microtissues to be used as a surrogate for xenografts, in conjunction with the Virtual Tumor™, for designing new drug regimens, testing possible schedules for combinations of different drugs and prioritizing the most effective drug combinations.
Reference: PAGE 21 (2012) Abstr 2450 [www.page-meeting.org/?abstract=2450]
Poster: New Modelling Approaches