Razvoj in validacija metod za načrtovanje zdravljenja raka z metodami na osnovi elektroporacije

 

Research project funded by the Slovenian Research Agency.

Članica Univerze v Ljubljani

UL Faculty of Electrical Engineering

Šifra
Z3-7126
Naziv projekta
Development and validation of treatment planning methods for treating cancer with electroporation based therapies
Obdobje
1.1.2016 – 31.12.2017
Letni obseg
1 FTE
Vodja

Bor Kos

Veda
Medicine - Oncology
Sodelujoče RO

sodelujoče RO

Vsebinski opis projekta

Electroporation based biomedical applications use electroporation, which is achieved by application of high voltage electric pulses to biological cells, as a physical mechanism to modulate the permeability of the cellular membrane. Electrochemotherapy is a treatment modality with local anti-tumour effect based on using electroporation to increase cellular uptake of cytotoxic drugs, such as bleomycin and cisplatin. Irreversible electroporation uses electroporation alone to disrupt the cause cell death.

Both treatment modalities require specialized pulse generators, which are already available on the market. These pulse generators are required to generate short high voltage pulses of up to 3000 V and 50 A in amplitude; pulse duration is typically 100 microseconds. The electric pulses are delivered via needle electrodes which are inserted into and around the target volume to be treated. These needles need to be positioned correctly and adequate voltages need to be applied to them in order to ensure coverage of the target volume with sufficiently strong electric field.

The goal of the proposed project is improving the safety and efficacy of elecrochemotherapy and irreversible electroporation for treatment of deep-seated tumours. We will achieve this goal by improving and validating treatment planning methods for instructing physicians on optimal execution of the electroporation-based treatments. We have previously developed methods for treatment planning and individualized optimization of treatment plans for electroporation based treatments, however those methods are limited in their accuracy by several uncertainties in the input parameters. To address the issue of increasing the availability and acceptance of treatment planning for electroporation based treatments, the existing methods of treatment planning need to be improved in accuracy and robustness.

The proposed project is structured in three work packages. In WP 1 we will support clinical studies which use electrochemotherapy for treatment of deep-seated tumours by preparing patient specific treatment plans; in WP 2, we will perform measurements of critical properties of tissues on ex vivo tissue to improve the scientific knowledge in the area of tissues under the influence of strong electric fields; in WP3, we will improve and validate the numerical patient-specific treatment planning methods to make them more accurate and perform a thorough robustness analysis of the developed treatment planning methods to ensure that they can be executed correctly and that expected and reasonable deviations from the treatment plan do not cause a drop in efficiency of the treatment.

The proposed project is designed to improve, validate and provide a rigorous robustness analysis of treatment planning methods for electrochemotherapy and irreversible electroporation of deep seated tumours. The project will therefore contribute to better acceptance and unification of treatment planning methods in the wider medical community. The technology being developed in the scope of the proposed project will be in many cases the only option for improving the quality of life and extending the life-span of the patients enrolled in the clinical studies. Through the improvements in treatment planning, success rate of the treatments and a wider availability of the treatments, the technology has the potential to reduce costs associated with treatment of patients with tumours or metastases in the liver and other organs.

Reaching the project objectives will result in increased safety and efficacy of electrochemotherapy and irreversible electroporation by reducing the probability of unwanted effects of treatment and improving the treatment outcomes through a better control of the electric field distribution in target tissues.

Sestava projektne skupine

link na SICRIS

Faze projekta in njihova realizacija

WP 1

Eleven patient specific treatment plans were prepared in the course of the year 2016. An innovative method of coupling treatment planning methods with optical navigation was presented at the international conference BioEM 2016 in a presentation entitled: “Electrochemotherapy with optical navigation for improved accuracy of treatment plan execution”; authors: Bor Kos, Aleš Grošelj, Maja Čemažar, Jure Urbančič, Maša Bošnjak, Biserka Veberič, Primož Strojan, Damijan Miklavčič & Gregor Serša.

During treatments using electrochemotherapy, currents and voltages are measured. This is being used for model validation and improvement of treatment planning methods. Currently, a manuscript is being prepared entitled “Ultrasound verification of the tumor coverage with electric field for effective electrochemotherapy”; authors: Nina Boc, Ibrahim Edhemović, Bor Kos, Maja Mušič, Erik Brecelj, Blaž Trotovsek, Maša Bošnjak, Damijan Miklavčič Maja Čemazar, Gregor Serša.

WP 2

We have initiated procedures for extending permission for use of animal tissues in experiments from pig ears to other tissue: pig liver and muscles. An automatic system for switching the experimental sample between a high voltage electroporation pulse generator and a precision LCR meter was developed. The system is controlled by a personal computer, which also logs the data and stores them for later analysis. The system was also upgraded with additional temperature measurement probes, which will allow also the validation of models of heating during electroporation.

WP 3

Existing models for predicting response of electroporation based treatments have focused on finding appropriate reversible or irreversible electroporation thresholds. This approach is limited by the fact that it is an approximation which neglects the transient region, where some cells are affected by the therapy and some are not. Additionally, the electroporation thresholds are dependent on the number of pulses. An improvement of this models is a statistical model of cell death – the Peleg Fermi model. It was first developed for modeling microbial inactivation due to electric fields and has already been adapted to animal cells; in the scope of this project it was also first adapted to modeling electroporation in vivo. The results are published in the paper: Sharabi S, Kos B, Last D, Guez D, Daniels D, Harnof S, Mardor Y, Miklavčič D. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption. Radiol. Oncol. 50: 28-38, 2016.

This model has also been used in a study with collaborators from the Virginia Tech University, where it was adapted for predicting response of gliomas to irreversible electroporation. A manuscript has been prepared and submitted: »Predictive Therapeutic Planning for Irreversible Electroporation Treatment of Spontaneous Malignant Glioma«; authors: P.A. Garcia, B. Kos, J. H. Rossmeisl, Jr., D. Pavliha, D. Miklavčič, R. V. Davalos.

In the scope of this work package, the mechanism of Electromotive Drug Administration (EMDA) for treatment of bladder cancer was also investigated, since it had been hypothesized that electroporation could be the mechanism responsible for the effectiveness of the method. The results have been published in the paper: Kos B, Vásquez JL, Miklavčič D, Hermann GGG, Gehl J. Investigation of the mechanisms of action behind Electromotive Drug Administration (EMDA). Peer J. 4: e2309, 2016.

Bibliografske reference

link na SICRIS