Tumor avatars developed to combat colorectal cancer

How to determine the most effective treatment for colon cancer? The response to chemotherapy varies greatly from one patient to another. A team from the University of Geneva (UNIGE) has developed a new method to test different drugs, without going through the body of the affected person and without resorting to animal experimentation. The researchers used organoids, miniature reproductions of organs and tissues, derived from patients and exposed to treatments. The results of these tests were then modeled. This approach, the results of which can be found in the Journal of Experimental & Clinical Cancer Researchopens the way to optimized and personalized therapies against various forms of cancer and other diseases.

With more than 1.4 million people affected each year, 700,000 of them fatally, colorectal cancer is the third most diagnosed cancer in the world and the second deadliest, only after lung cancer. Its treatment is mainly based on a combination of chemotherapies called FOLFOXIRI. However, its effectiveness varies from patient to patient and its side effects are significant. It also leads to progressive drug resistance in most patients.

How can chemotherapy combinations be tested and optimized for each patient without causing numerous side effects? A UNIGE team led by Patrycja Nowak-Sliwinska, Associate Professor in the Faculty of Pharmaceutical Sciences at the UNIGE Faculty of Sciences and a member of the Center for Translational Research in Oncohematology (CRTOH), has found the solution through the use of organoids. These three-dimensional cell structures, created in the laboratory, reproduce the structure and functions of certain tissues and organs.

They are almost like organs

“These microtissues are not organs as such,” explains George M. Ramzy, postdoctoral researcher at the School of Pharmaceutical Sciences of the UNIGE Faculty of Sciences and first author of the study. “They have some important physiological differences, such as not having a vascular or nervous system. However, they are very effective models for testing treatments.”

The researchers started with cancerous tissue taken from untreated patients at the University Hospitals of Geneva (HUG). By growing stem cells from these tissues, which gradually divided and organized into three-dimensional structures, the scientists were able to produce organoids, or tumoroids, from each patient’s tumor.

“We then tested different drugs on these models, without knowing their genetic background,” explains Patrycja Nowak-Sliwinska. These individual antecedents largely determine the effectiveness of the treatments. Therefore, the researchers started from scratch, basing their entire study on observing the response of cells in real time.

Fast, effective and personalized

These tumor avatars were exposed to a range of seven treatments currently in clinical use. Depending on the response of the organoid in each patient, the combination and doses of said treatments were adapted. All the results were mathematically modeled to predict the efficacy and optimal doses for each organoid, that is, for each patient.

These tests were carried out for two weeks. “This is a clinically relevant time frame: it is the time frame that the medical professional currently needs to choose a treatment after reaching the diagnosis,” says Patrycja Nowak-Sliwinska.

Thanks to a collaboration between the UNIGE research laboratory and EPFL, the researchers were able to determine the stage
of the tumor of each patient and the main mutations involved in the progression of the disease. This information is relevant and essential to better understand the choice and mechanism of action of each drug combination. “Each patient is different and requires a specific treatment,” adds Patrycja Nowak-Sliwinska.

This innovative approach, without animal models, has just been patented. It offers personalized treatment for many forms of cancer, but also for other diseases such as cardiovascular or viral diseases. Trials are underway for kidney cancer. For the research team, the next step will be to work on pre-treated colon cancer tumor organoids, which therefore show signs of resistance. The aim will also be to shorten the duration of the optimization process.

Source: UNIGE

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