Research And Grants

Targeting Diffuse Midline Glioma vulnerabilities as a therapeutic strategy.

Diffuse Midline Gliomas (DMGs), including Diffuse Intrinsic Pontine Gliomas (DIPGs), are among the most aggressive pediatric brain tumors and the leading source of mortality in pediatric oncology. The median life expectancy of these children remains below 14 months after diagnosis, and nearly none survive beyond the second year. All therapeutic approaches have failed, leaving radiation therapy as the sole palliative treatment that transiently ameliorates the disease. Therefore, finding a curative and feasible alternative for these children is of the utmost importance.  Delta-24-RGD is an oncolytic adenovirus genetically modified to replicate and kill tumor cells selectively while remaining harmless in normal tissues. This biotherapeutic agent has been recently tested in a small number of DIPG patients, validating its safety and showing clues of efficacy. In addition, analysis of patient samples demonstrated the effect of Delta-24-RGD in activating the patient’s immune response against the tumor. Unfortunately, the effect was only transitory, and all patients recurred. Additional genetic modifications of Delta-24-RGD have been explored to potentiate its anti-tumor effect, such as incorporating immunostimulatory transgenes. Despite these upgraded viruses being more efficient in promoting anti-tumor responses, the effect cannot be curative in all subjects. Here, we propose to refine the design of modified oncolytic viruses by considering the intrinsic peculiarities of DMGs. We will arm this virus with molecules that have the capability to trigger effective antitumor immune responses while maintaining a safe profile.  At the end of the project, we expect that the results yielded by this project will show a new, innovative, and efficient therapeutic approach based on oncolytic viruses for DMGs while maintaining a safe profile. These data should place us in a strong position to translate to the clinical scenario a new therapy for children with DMGs, and we expect to find that it offers these children a curative, safe, and feasible alternative.