Research based on bioengineering developed at the Oswaldo Cruz Institute (IOC/Fiocruz) is opening up innovative possibilities in the search for treatments for cancer and Chagas disease. The studies are based on the creation of three-dimensional (3D) cell cultures, called spheroids or organoids, capable of reproducing the characteristics of biological tissues.
Cancer and Chagas disease are the target of research using this technology. Among the latest results is the development of a model for testing personalized cancer therapies, called tumor chemogram. Work is also underway on a potential drug for treating cardiac fibrosis associated with infection by the parasite Trypanosoma cruzi, which causes the Chagas disease.
"Expertise in tissue bioengineering is an advantage for studies on therapeutic response and pathophysiological mechanisms. The spheroids reproduce what happens in the tissue in vivo in such a way that is closer to reality than a two-dimensional monolayer cell culture," explains Luciana Garzoni, researcher at the Laboratory of Molecular Virology and Parasitology and current deputy director of Research, Technological Development and Innovation at IOC/Fiocruz, who is leading the studies.
Personalized therapy
The project to develop the tumor chemogram will celebrate ten years in 2025. The initiative began in 2015, during a doctoral research carried out in the Graduate Program in Cellular and Molecular Biology at IOC/Fiocruz by the current postdoctoral student Laura Lacerda Coelho at the Institute, under Luciana's supervision.
For the test, tumor organoids are produced in the laboratory from cells isolated from tumor fragments. Placed in culture plates, these cells spontaneously reorganize themselves into three-dimensional structures, forming microtumors.
As they reproduce morphological and functional characteristics of tumors, they can be used to assess the power of action of different drugs, pointing out those with the best performance against the specific tumor of patients.
According to the researcher, the aim is to enable personalized therapy in search of a more effective treatment. "The test is a breakthrough in the context of translational oncology, which seeks to apply advances in basic research to solve challenges in the diagnosis and treatment of cancer. Even if two patients have the same type of cancer, the way each tumor responds to therapy can vary. In this scenario, the purpose of the tumor chemogram is, based on a sample of the patient's own tumor cells, to assess which drug would be most effective for their treatment," she says.
According to the researcher, the methodology for producing the tumor chemogram was tested in pre-clinical trials using cells collected directly from animal tumors, which are considered experimental models. It has also been validated with human tumor cells, which are isolated from patients and adapted to grow continuously in the laboratory. These supplies are procured from a specialized companies and are widely used in research.
The innovation has reached technological readiness level 6 (TRL 6), with the demonstration of a fully functional prototype. "To advance the technology, we need to start large-scale tests under good laboratory practice (GLP) conditions, which will be taking place in the first half of 2025, using cells collected from patients' tumors," the researcher points out.
The group recently published a study based on this methodology, which reproduced, in the laboratory, the process of breast tumor metastasis, which occurs when cancer spreads throughout the body.
Published in the scientific journal Biology, the study showed that the 3D model reproduces the migration of tumor cells and the change in the expression of proteins that are key to the start of the metastatic process, in a similar way to what happens in tumors in patients.
"The epithelial cells of the spheroid acquire mesenchymal characteristics, becoming capable of migrating and detaching from the tumor. This is one of the processes involved in the development of metastases, when tumor cells establish in other tissues. Thus, we have an excellent model for assessing new antimetastatic drugs," says Luciana.
The work included tests with the drug doxorubicin, which is frequently used in the treatment of breast cancer and which showed an important antimetastatic effect, inhibiting the epithelial-mesenchymal transition and the migration of tumor cells.
At IOC/Fiocruz, scientists from the laboratories of Innovations in Therapies, Teaching and Bioproducts; Thymus Research; Pathology; and Epidemiology of Congenital Malformations were involved in the work. Researchers from the Fluminense Federal University (UFF) and the National Cancer Institute (Inca) also took part.
According to the researcher, the next step is to move forward with the clinical study to characterize the tumor chemogram as a predictor of therapeutic response, in an environment that simulates real conditions of use, foreseen in the postdoctoral project developed by biologist Gabriela Vieira.
Discoveries in mini hearts
In addition to research into cancer, studies into Chagas disease have progressed using organoid trials. In this type of study, one of the main advantages of the three-dimensional model is that it reproduces the process of fibrosis and hypertrophy that affects the heart muscle in the chronic form of Chagas' disease, as previously demonstrated in scientific articles published by the group.
In around 30% of patients, the presence of the parasite and the persistent inflammatory process in the heart damage the heart muscle, which leads to the development of fibrosis and scarring. Excessive scarring causes changes to the architecture of the heart tissue, impairing its functioning and potentially causing problems such as arrhythmia and heart failure.
To better understand this process and look for new therapies, the researchers developed an organoid model called a mini heart, made up of heart cells. With a spherical shape, cardiac organoids are 3D cell cultures capable of spontaneous contraction and cellular and molecular interactions similar to those observed in the heart muscle.
"When we infected the mini hearts with T. cruzi, we were able to reproduce the fibrosis process not only at the molecular level, but also at the structural level. This allows us to test compounds to try to block or reverse this process," says Luciana.
In experiments with T. cruzi-infected mini hearts, the group has already identified compounds with antifibrotic activity. The latest research was carried out by biomedical scientist Clara Seydel, under Luciana's guidance, during her master's degree in the Graduate Program in Cellular and Molecular Biology at IOC/Fiocruz. In the study, a positive result was observed with a drug that managed to reduce hypertrophy and the expression of proteins involved in fibrosis in the heart tissue.
"These results suggest that the model has great potential for the study of new therapeutic approaches for the treatment of cardiac fibrosis in Chagas disease," says Luciana. The researcher adds that the clinical use of the drugs already tested still depends on other stages of research, including tests on animals and patients.
Further, the mini hearts can contribute to studies on the formation of cardiac blood vessels, as the scientists have shown that organoids produced with mesenchymal stem cells and endothelial cells develop blood vessels, indicating potential for studies in the field of translational cardiology.