Electroporationbased therapies (irreversible electroporation and electrochemotherapy) provide interesting alternatives to standard ablative techniques, particularly for deep seated tumors near vital organs or important vessels. However these nonthermal techniques, which preserve the tissue scaffold and reduce bleeding are still mostly limited to cutaneous and subcutaneous tumors. Such limitation is mainly due to the technical difficulties raised by these therapies for which the a priori determination of the treated zone is trickier than for standard ablative techniques. Moreover, these therapies suffer from the lack of biological knowledge concerning the local relapse and the biological features of the region affected by the electric field. Moreover appropriate post treatment protocols to evaluate the tumor response are still missing. The project NUMEP, composed of computer scientists (Inria MONC), biologists (IPBS) and radiologist (CHU J. Verdier), proposes to provide new insights in understanding biologically and in modeling numerically the effect of electroporationbased therapies on tumors, in order to provide numerical tools enriched by biological knowledge that help the clinical applications of electroporation in cancer treatment. For the sake of coherence we will focus on hepatocarcinoma to the liver. Based on medical image acquisition during the procedure (from Carm Cone beam CT) we plan to provide accurate numerical tools for realtime simulations of the electric field distribution, which accounts for the exact position of the electrodes. We also plan to predict the different zone affected by the treatment based on new biological knowledge of electroporationbased therapies thanks to designed experiments on spheroids and mice. The longterm goal is to propose numerical tools that will be incorporated in the medical image processing tools to superimpose the electric field distribution and the affected zones on the image during the treatment procedure.
NumEP is lead by C. Poignard, research scientist at Inria. The local coordinators are O. Séror, PhD-MD Prof. at CHU J.Verdier, and M.-P. Rols, CNRS Research Director at IPBS.
The project NUMEP is organized into 3 main tasks: Task 1 is devoted to mathematical and biological models for spheroid electroporation. Spheroids provide an interesting in vitro tumorlike biological model which can mimic several aspects of tumor organization. In particular, the distribution of the electric field in tumors can be well understood thanks to spheroids. We propose to model the influence of pulsed electric fields on the growth of the spheroid, and we will investigate the changes in the field threshold for IRE with respect to the type of spheroids. In particular, it is crucial to determine the differences between healthy cells, proliferative and quiescent cancer cells, as well as the influence of IRE on the regrowth of the spheroids. We will then investigate and quantify the efficiency of ECT and geneelectrotransfer on spheroids composed with human tumor cells, healthy cells or both. Task 2 consists in modeling electroporationbased therapies for in vivo experiments. We aim at characterizing by in vivo experiments the regions affected by the electric field, in order to compare with the results of the modeling. This task will make it possible to determine the region irreversibly affected by the field between the electrodes. This will possibly provide qualitative characterization of the edema region that appears on MRI. We will also evaluate tumor growth and relapse after electroporationbased therapies (IRE and ECT). Pushing forward the studies of Mir’s group (A lSakere2007, Calvet2014a, Calvet2014b) , we propose to investigate whether or not the hallmarks of immune response are induced by IRE and ECT on hepatocarcinoma’s bearing mice . We plan to focus on such cancer because it is the disease treated by IRE at CHU J. Verdier. Benefiting from the experience of IPBS on DNA vaccination, we project to propose new strategies to generate immune response with electroporationbased therapies. In particular, we are confident that the edema zone generated by the pulsed electric field would be crucial in emphasizing such an immune response. Task 3 concentrates the clinical goals of the project. The aim of the task 3 is to propose new models and efficient numerical schemes based on these clinical data. Using the exact localization of the electrodes from the medical images, we will develop numerical tools that will give the electric field distribution, and determine the zone treated by IRE, in order to provide efficient tools useful to physicians. We plan to push forward the « standard » numerical studies of IRE (which only provides a computation of the electric field in a homogeneous medium), we plan to benefit from the knowledge acquired by the first two tasks to provide numerical tools that characterize in realtime simulations the distribution of the electric field as well as the thermal, irreversibly and reversibly electroporated regions. In order to avoid the variability of due to the disease, we will focus on the medical data for HCC tumors located to the liver. Interestingly, the partner CHU J. Verdier has acquired since 2 years a panel of more than 60 patients with HCC treated by IRE, which is still increasing since IRE is routinely used for such patients.