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| Differentiated hepatic cells growing in a flask re-gain the appearance of cells present in liver. Image Credit: © FAMOL, UNIGE |
Overcoming acquired treatment resistance is one of the major challenges in the fight against cancer. While combination therapies hold promise, their toxicity to healthy tissue remains a major hurdle. To anticipate these risks, researchers at the University of Geneva (UNIGE) have developed in vitro models of the kidneys, liver, and heart – three organs particularly sensitive to such therapies. This fast, animal-free approach paves the way for safer evaluation of new treatments. The findings are published in Biomedicine & Pharmacotherapy.
Recent advances in immunotherapy, targeted therapies, and gene therapies have significantly improved survival rates for patients with cancer. However, over time, many tumors develop resistance to these treatments, undermining their effectiveness. This phenomenon, known as ‘acquired resistance’, has become one of the major challenges in oncology.
In addition to saving a significant amount of time, this approach is fully in line with the 3R principle, which aims to ‘reduce’, ‘replace’, and ‘refine’ the use of animal models.
To overcome this resistance, the most promising strategies involve combination therapies using multiple drugs. While these approaches enhance therapeutic effectiveness, they often cause serious toxicity in healthy organs and tissues, restricting their clinical application. To address this risk, a team at the University of Geneva (UNIGE) has developed a laboratory platform to rapidly test the toxicity of such drug combinations without using animal models.
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| Patrycja Nowak-Sliwinska, Assistant Professor, School of Pharmaceutical Sciences, UNIGE Faculty of Sciences. Photo Credit: Courtesy of Université de Genève |
Three modeled organs
“This platform models the human kidney, heart, and liver in vitro, as clusters of cells derived from human tissue. These three organs are especially vulnerable to drug toxicity,” explains Patrycja Nowak-Sliwinska, associate professor in the School of Pharmaceutical Sciences at the UNIGE Faculty of Science and member of the Centre for Translational Research in Onco-Hematology (CRTOH) at the Faculty of Medicine. ‘‘With this platform, we can study how new drug combinations interact with these organs and then decide whether it is justified to move on to in vivo testing in humans or animals.”
Using this approach, scientists from the School of Pharmaceutical Sciences, in collaboration with the UNIGE Faculty of Medicine and Geneva University Hospital (HUG), tested two specific drug combinations currently in development, C2 (erlotinib HCl, dasatinib, tubacin, tacedinaline) and REMP (erlotinib HCl, parthenolide, metformin HCl, RAPTA-C). “For example, we found that C2 exhibited significant liver toxicity. This indicates that proceeding in vivo testing with this combination may not be appropriate,” explains the researcher.
A step forward for the ''3Rs''
This method is particularly fast, as it takes only two weeks to obtain results, compared to 10 weeks or more for tests carried out using animal models. ‘‘In addition to saving a significant amount of time, this approach is fully in line with the 3R principle, which aims to ‘reduce’, ‘replace’ and ‘refine’ the use of animal models in research,’’ the scientists point out.”
Ultimately, the next step will be to extend the model to other organs and further customize the platform. Researchers plan to add new organs to the system and, in the longer term, to move beyond standard cell lines by using patient-derived cells. This development would allow drug combinations to be tested for toxicity in a more personalized way.
Published in journal: Biomedicine & Pharmacotherapy
Title: Leveraging multi-organ models for drug combination therapy safety
Authors: Valentin Mieville, Jakub Gubala, Seungsu Han, Marie Ota, Mireia Andreu-Carbó, Filippo Molica, Daniel Benamran, Brenda R. Kwak, Massimo Valerio, and Patrycja Nowak-Sliwinska
Source/Credit: Université de Genève
Reference Number: bmed121625_01
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