2024-03-11 10:45:46
The incidence of retinoblastoma (the most common pediatric eye cancer) in the world is 1 case in every 17,000 live births. Retinoblastoma can be eliminated when detected early and is usually sensitive to chemotherapy. However, the prognosis worsens if the cancer spreads mainly to the central nervous system: in these cases, up to 9 out of 10 patients are not cured despite chemotherapy, radiotherapy and surgery.
Specialists from the National Scientific and Technical Research Council (CONICET) of Argentina at the Garrahan Hospital and colleagues from other institutions have managed to develop for the first time a preclinical model and primary cell cultures that reproduce the biology of metastatic retinoblastoma and that will be used to design innovative treatments. that can cure these patients. The team is led by Santiago Zugbi, from the JP Garrahan Pediatric Hospital and CONICET.
“It is essential to advance in the knowledge of why the tumor spreads, to determine the molecular risk factors that control this process. The preclinical models that we managed to generate will be useful to evaluate new therapeutics and finally, find new treatments for this population that today lacks alternatives,” says Paula Schaiquevich, co-author of the study, researcher at CONICET and director of the Innovative Treatments Unit at Garrahan Hospital. .
In developed countries, this type of tumor is usually detected in time, but in middle and lower-middle income countries, as a consequence of late diagnosis, limitations in access to treatments, cultural factors and other variables, more than half of Affected children are diagnosed with metastatic disease, that is, when the tumor has spread outside the eye to other organs and tissues.
Schaikevich emphasizes the importance of developing a preclinical model for the study of retinoblastoma. This type of cancer, like most pediatric malignancies, is a rare disease. “Therefore, it is very difficult to carry out clinical studies to identify new treatments that include a significant number of patients. Since there are ‘few’ patients, it is difficult to carry out several clinical studies to identify which would be the ‘best’ therapy. To this end, these models, like the one we have developed, are very important because they allow us to evaluate and ‘filter’ by selecting the treatments that are the most promising so that they can later be evaluated in studies in patients,” he points out.
Members of the research team. (Photo: Verónica Tello / CONICET. CC BY 2.5 AR)
Before the new study, there were no tumor cells from metastatic retinoblastoma patients that could be grown in the laboratory, as well as laboratory animals (mice) with this type of tumor in which tumor progression can be studied and new drugs tested. .
“In this study, we developed cellular and animal models with this type of tumor and after evaluating them, we know that similar histological, molecular and pharmacological characteristics are presented to the patients. To do this, we developed molecular, genomic, histopathological, and pharmacological tests that reflected different behavior for each model, but similar to what happens in the patient from whom we obtained the tumor cells,” explains Schaiquevich.
In different analyses, the CONICET scientist and colleagues found that the tumors grew and invaded organs and tissues in the animal, as occurred in the patients from whom the tumor cells were taken. “They are reliable models and reproduce the biology of the patient’s tumor from which they are derived. Laboratory studies even show us that tumor cells in the laboratory respond to chemotherapy as was observed in patients,” says Schaiquevich. And he adds: “This way we can use these models to discover new treatments, whether they are new drugs or those that are already on the market but are used for the treatment of other pediatric tumors or even for other diseases.”
A very important aspect of the project “is that we generate local capacities in our country for the genomic and molecular evaluation of retinoblastoma and the development and characterization of preclinical models of this tumor. The tools learned can be applied to develop new models in other pediatric tumors,” said Schaiquevich.
Previous studies, led by the CONICET researcher, have made it possible to improve the treatment of intraocular retinoblastoma (non-metastatic) in one eye, bilateral (both eyes) and refractory (when the patient does not respond to standard treatment).
Previously, for intraocular retinoblastoma, chemotherapy was administered intravenously, but the drugs, in addition to eliminating cancer cells, damaged healthy tissues. “With the retinoblastoma research group, we carried out preclinical studies that allowed us to optimize therapeutic regimens and define which chemotherapy drugs to use together in children affected with intraocular retinoblastoma to achieve greater treatment effectiveness and reduce the probability of adverse events, even serious ones that “They can endanger the patient’s life,” explains Schaiquevich. And he continues: “These studies allowed us to verify the effectiveness and safety of two chemotherapy administration techniques (superselective intra-ophthalmic artery chemotherapy and intravitreal chemotherapy) that were developed in Japan, the United States and Switzerland and whose purpose was to administer chemotherapy mainly to the tumor. to avoid systemic side effects (in the blood and other normal tissues). The results of our research, described in international scientific journals, allowed the team of oncologists, ophthalmologists and neurointerventionists at the Garrahan Hospital to use these procedures and successfully treat boys and girls with intraocular retinoblastoma.”
“Having CONICET research groups within the hospital for more than 15 years has been very beneficial in applying effective therapies to pediatric patients with intraocular retinoblastoma. This interdisciplinary work allows science to help solve challenges that we face in the clinic,” says Pedro Zubizarreta, pediatrician and head of the Garrahan Hematology and Oncology Service. And he concludes: “Boys and girls with metastatic retinoblastoma have a reduced chance of cure. For this reason, the development of new technologies and therapeutic possibilities for this group of patients is necessary. The experimental model developed by Schaiquevich and colleagues to understand the biology of this tumor when it spreads aims to provide new knowledge that contributes to this objective.”
The development of the preclinical model for the study of metastatic retinoblastoma is part of a line of research developed within the framework of a joint work coordinated and integrated by researchers, CONICET fellows and fellows at the Garrahan national reference pediatric hospital, in the Institute of Biochemical Research of Buenos Aires (IIBBA, CONICET-Fundación Instituto Leloir), specialists from international institutions, and Garrahan medical staff.
The study is titled “Establishment and Comprehensive Characterization of a Novel Preclinical Platform of Metastatic Retinoblastoma for Therapeutic Developments.” And it has been published in the academic journal Investigative ophthalmology & visual science. (Source: Bruno Geller / CONICET. CC BY 2.5 AR)
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