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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - OPTIM (Optimized drug combinations for effective cancer treatment: a personalised approach.)

Teaser

Summary

This project aims to improve the treatment of colorectal carcinoma (CRC), as treatment options after first line chemotherapy are desperately needed. The key to improvement of cancer therapy resides in optimal combination of drugs. Optimally combining drugs is non-trivial due to the large number of possibilities, especially when more than two drugs are combined at various doses. In the current research program it was proposed to use a differential evolution guided stochastic search algorithm to guide the way in finding optimal combination therapies.

A new screen for optimal targeted combination treatment of advanced CRC will be performed. A series of 7 genetically different human CRC cell lines was used in this screen, thus simulating personalized treatment. The optimized 3-4 drug combinations were optimized in a series of in vitro experiments. The screen was performed simultaneously in non-cancerous colon cells to control eventual toxicity. The cell-type specific drug combinations were validated in 3D heterotypic co-culture models and translated into preclinical CRC mouse models. Their activity was compared to the one of the standard chemotherapy regimens. The development of a method for a personalized screen using freshly isolated tumor cells is being executed if a long-term aim of preparing the technology for a possible application in the clinic.

Work performed

In order to ensure enhanced selectivity towards malignant cells and reduce the chances of increased drug toxicity, the optimization was performed based on the Â« therapeutic window Â» between malignant and non-malignant cells using the objective function described below as an optimization criterion:

therapeutic window = (% CTRL non-malignant cell viability) - (% CTRL cancer cell viability)

Moreover, we included clinically achievable drug plasma concentrations in patients, which should ensure the further clinical accuracy and safety profiles of our drug mixtures.
These changes modernized and improved the original project design, resulting in much more information about drug interaction and drug efficacy.
Using an initial set of eleven targeted compounds, a screen for optimal drug combination treatment of advanced CRC was performed in a series of seven genetically different human CRC cell lines thus simulating personalized treatment. In all screens, the therapeutic window was optimized in comparison to a non-malignant cell line (normal human colon cells) in order to control the safety profile of the optimization. Using the s-FSC platform the cell type specific optimal 3- to 4-drug mixtures were identified for all CRC cell lines.
In order to execute the WP2, the collaboration with the clinical partners at the Clinical Pathology Service (HUG) and Clinical Oncology (HUG) have been initiated. The SwissEthics protocol was approved for isolation of cells from the freshly resected CRC tumor tissues in order to perform a similar screen in patient-derived CRC cells.

Final results

In my search for the new tools to advance the drug screen optimization we developed three-dimensional (3D) cancer models. With the aim to develop a platform for drug screening and studying drug efficacy in colorectal carcinoma (CRC), we optimized a 3D co-culture sphere system, in which the following components were integrated: (i) spheres composed from patient-derived CRC cells, (ii) sphere consisting of CRC cells interspersed with endothelial cells (ECs) and fibroblasts (FBs), two major cell types interacting with tumor cells in the tumor micro-environment. This platform is ready to be used for optimized drug combinations validation.