The drosophila cancer model
Transgenic flies helped to find a cure for a patient with colorectal cancer
Daria Spasskaya, N+1
American researchers have published in Science Advances the results of the first case of the appointment of personalized therapy to a patient with colorectal cancer, selected with the help of fruit flies (Bangi et al., A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer). The analysis of mutations in the tumor allowed him to create an individual model of bowel cancer on drosophila and pick up an unexpected combination of drugs on flies, which eventually helped the patient.
Drawings from an article in Science Advances.
According to researchers from the Icahn School of Medicine at Mount Sinai Medical Center (USA), a 53-year-old patient with metastatic bowel cancer was unsuccessfully treated with two courses of chemotherapy. DNA was isolated from a sample of his tumor and analyzed for the presence of oncoassociated mutations. In total, more than a thousand mutations were found in the tumor, compared with DNA from blood, but the researchers were able to select nine of the most significant ones that would affect the main signaling pathways. It includes mutations in the KRAS oncogene, which are associated with almost half of intestinal tumors, and mutations that suppress the main oncosuppressor genes.
Since the main cellular signaling pathways are conservative in all animals, the researchers were able to reproduce the genetic features of the patient's tumor on drosophila. To do this, the same mutation was introduced into the fly homologue of the KRAS gene as in the patient, and the expression of oncosuppressors was suppressed using microRNAs synthesized only in the intestinal cells of flies.
The intestine of a transgenic model fly (right) compared to the control (left).
After creating an individual fly model of the tumor, the researchers went through the library of drugs approved for the treatment of cancer in search of a drug that would increase the survival of transgenic flies. On the first attempt, no such substance was found. Then the researchers chose a kinase inhibitor drug that acts on cells with mutations in the KRAS gene (trametinib) and began to combine it with other drugs, not only with approved ones, but also with those that showed at least some anti-cancer activity in models. It turned out that trametinib works in combination with drugs of the bisphosphonate group, which are usually prescribed to maintain bone mineral density (ibandronate and zoledronate). Following the results of the experiment, the council of oncologists decided to prescribe a combination of trametinib with zoledronate to the patient.
The new combination of drugs helped, after three months of therapy, the volume of cancer foci in the man decreased by half. Unfortunately, after that, the progress in treatment stopped. In total, the experimental treatment lasted 11 months, after which the patient was prescribed regorafenib (another kinase inhibitor) as the fourth line of therapy.
Despite only partial success of the treatment, the authors emphasize that they have managed to create the most complex model to date, reproducing the genetic landscape of the tumor. Other methods of screening drugs involve creating a tumor culture in vitro or inoculating it to mice – this is a more comprehensive approach, but it can be much more time-consuming and time-consuming.
Earlier we told how scientists suggested using Danio rerio fish as a personalized model of colorectal cancer. The analysis of the sensitivity of the tumor took only four days and showed a good correlation with the results of treatment of patients.
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