Conducted and financed by the Gaslini Institute of Genoa, the initiative aims to delve deeper into the genetics of this rare tumor in order to develop precision therapies
Well over 90% of all cases of malignant tumors of the nervous system can be attributed to the category of neuroblastomiwhich are responsible for almost 15% of childhood cancer deaths: it is therefore a question of very aggressive rare tumors, supported by a complex genetic framework. Although innovative approaches that exploit the potential of CAR-T cell-based therapies, the therapeutic protocol currently available against neuroblastoma is still limited; nevertheless researchers are convinced that to develop new treatment strategies it is essential to start from the genetics of the tumor. Driven by this belief, the PREME Project was born.
Financed by“Giannina Gaslini” Institute of Genoa and carried out under the direction of the research group of Dr. Mirco PonzoniHead of the Laboratory of Experimental Therapies in Oncology of the Ligurian Pediatric Institute, PREME is the first Italian multicenter prospective precision medicine protocol focused on neuroblastoma. It is therefore a project that aims to overcome the tumor phenotype, searching for genetic elements common to the different forms of disease to be used to set up highly personalized treatment programs. In fact, most neuroblastomas are characterized by gene amplifications MYCN or rearrangements of TERT and many have mutations in their genes ALK e ATRXagainst which targeted treatments could be adopted.
Immunotherapy is a sector that holds great hopes in the fight against neuroblastoma: proof of this are the anti-GD2 CAR-Ts developed in the Cell Factory of the Bambino Gesù Pediatric Hospital, under the supervision of prof. Franco Locatelli, and intended for children affected by relapsing or treatment-refractory forms. However, it will be necessary to better stratify patients and administer specific treatments to them understand the meaning and extent of all the mutations involved in the pathogenesis of neuroblastoma. For this purpose, the PREME Project was developedon which they are collaborating CEINGE – Advanced Biotechnologies “Franco Salvatore” of Napleswith the research team of professors Mario Capasso and Achille Iolasconand the geneticists of“Federico II” University of Naples.
“The primary objective of PREME is represented by the genomic characterization of samples from patients affected by neuroblastoma at diagnosis, in cases of refractoriness to first-line treatment or in relapse, for the development of innovative precision medicine therapies”, they explain Chiara Brignole and Fabio Pastorino, the two senior researchers of the Gaslini team, as well as responsible for the execution of the project. “PREME creates tailor-made therapies based on the genetic and molecular characteristics of individual tumors, thus improving the chances of success and effectiveness of treatments on young patients. All this thanks to the use of cutting-edge methodologies and the skills of a multidisciplinary team made up of biologists, geneticists, clinicians and bioinformaticians”.
A first sample of the potential inherent in this research approach has appeared in the pages of the magazine Journal of Translational Medicine: Italian researchers made use of exome sequencing methods, as well as a battery of genetic panels and sophisticated transcriptome analyses, on samples obtained from 18 patients with neuroblastoma to identify possible disease biomarkers with which to monitor responses to treatment, create tumor models alive on which to study selected oncogenes, define the most effective combinations of drugs and develop bioinformatic approaches through which to analyze the evolution of the tumor and design precision therapies to target it. A ‘tailored’ system to deal with a tumor whose pathogenesis, even today, is not completely known. “Thanks to new generation sequencing techniques and sophisticated bioinformatics analyzes conducted at CEINGE and CIBIO of the University of Trento, it emerged that 84% of neuroblastoma patients had genomic alterations amenable to therapeutic intervention“, explains Mario Capasso, leading the CEINGE bioinformatics team. Two-thirds of these cases were classified as “very high priority,” opening the possibility of benefiting from already approved drugs or new therapeutic agents in development.
“Molecular targeted therapy was applied to four patientswhile genetic counseling was offered to two patients with germline mutations that indicated a familial predisposition to the development of tumors”, underlines Fabio Pastorino, presenting the strengths of the project, which demonstrated how a capillary and complete molecular analysis is feasible on a national scale: the biological samples of the patients, coming from various Italian pediatric oncology centers, were characterized by the Laboratory of Experimental Therapies in Oncology and by Gaslini’s Pathological Anatomy and, subsequently, subjected to analysis at CEINGE and CIBIO for the identification of somatic mutations potentially targetable by targeted drugs. Finally, they have been used for the development of preclinical models of neuroblastoma (xenografts derived from patient cells and 3D tumor spheroids obtained from both tumors and cancerous cells infiltrating the bone marrow) capable of summarizing the histological and genomic characteristics of tumors of origin. “In the work just published we have demonstrated that these models maintain the genetic and immunophenotypic characteristics of the patients of origin, contributing to the creation of a very valuable local collection of biological samples for the validation of the anti-tumor effects of molecular-guided drugs and potential combinations therapeutic,” he adds Chiara Brignole.
There was great satisfaction among the researchers who believed in PREME, born as a research project in 2019 and transformed, in 2022, into a clinical protocol co-financed by the Italian Foundation for the Fight against Neuroblastoma and the OPEN association (Pediatric Oncology and Neuroblastoma) . “PREME marks a decisive advancement in optimizing the care and treatment of neuroblastoma”, conclude Mirco Ponzoni, head of the Laboratory of Experimental Therapies in Oncology of the Gaslini Institute. “The application of targeted therapies, adapted to the specific mutations present in patients, the personalization of treatment and the use of advanced preclinical models transform translational research into tangible benefits for patients, improving their prognosis”.