Development of new effective strategies and innovative drug delivery systems for pediatric diffuse midline glioma

Diffuse midline gliomas (DMGs) are aggressive brain tumors that primarily affect children and young adults. They are located in midline structures of the brain making surgical resection difficult, and represent the most lethal subtypes of pediatric high- grade gliomas, aggressive neoplasms that originate from glial lineages in the developing central nervous system (CNS). DMGs are associated with a very poor prognosis, with a median survival time of 9-12 months remained unchanged despite decades of dedicated clinical trials. Therefore, current treatment options for DMGs are very limited and there is an urgent need for more effective therapies.
Because of their infiltrative nature and localization in vital areas of the CNS, DMGs are typically unresectable thus limiting the availability of specimens for extensive molecular and cellular characterization. Nevertheless, significant progress has been made in recent years in understanding the biology of DMGs and this knowledge has led to the development of new targeted therapies that are currently under clinical evaluation. It is noteworthy that many of the genetic and epigenetic alterations that occur in DMGs are also found in other brain tumors, such as glioblastomas and pediatric high-grade gliomas, thus making DMGs a useful model system for other types of brain tumors as well.
Recently, the mitochondrial serine protease ClpP (proteolytic subunit of caseinolytic protease) and dihydroorotate dehydrogenase (DHODH) have been shown to play important roles in the pathogenesis of DMGs, and targeting both enzymes has emerged as a promising strategy for the treatment of brain tumors, including DMGs.
Detailed characterization of the interactions between neoplastic cells and their microenvironments, including immune and stromal cells, is essential to understand tumor pathogenesis and to develop more effective therapies. This project will pursue three main objectives: i) to characterize the spatial distribution of key tumor and immune cell subpopulations in human DMG samples; ii) to develop new therapeutic strategies for DMGs by screening molecules already in phase III and IV clinical trials, as well as large libraries of commercial compounds, to identify potential new molecules targeting of ClpP or DHODH that will be tested in 2D and 3D in vitro models of DMGs and by testing temporary LIPUS- induced BBB disruption and drug delivery by EVs and other nanocarriers to improve BBB penetration; iii) to determine the effects of drug treatments (alone or in association with LIPUS) on tumor growth and on the spatial distribution of the phenotypic and molecular features of cells in animal DMG models.
This research project brings together researchers with diverse expertise who join forces and different experiences to address an unmet need in oncology: the identification of an appropriate and effective therapy for DMGs.
The proposed activities will provide a detailed characterization of the cellular landscape of DMG, useful for the development of new therapeutic strategies and/or the identification of useful biomarkers. They will also allow the identification of new molecules active against DMG and provide insights into the use of LIPUS and EVS to improve BBB permeability and facilitate drug delivery to brain tumors.
The central goal is to generate proof of concept evidence to support the rapid clinical development of better treatments not only for this devastating tumor, but also for other types of brain tumors.