3 years duration, INCA grant AAP PLBIO 2014, coordinator J. Grill (IGR)

Brain tumors are the leading cause of cancer-related mortality and morbidity in children, adolescent and young adults. Diffuse Intrinsic Pontine Glioma (DIPG) is the most severe form, killing most of if not all affected children in the first two years after diagnosis. Its infiltrative nature and its location deep in the brainstem make this tumor inoperable. Chemotherapy is inefficient and radiotherapy brings only a transient symptom relief. The development of new therapies has been hampered by the lack of biological information on DIPG and the absence of preclinical models. Erroneously assimilated to the glioblastoma counterparts seen in adults, its biology remained mysterious until recent publications that clearly marked down DIPG from other type of gliomas. They are individualized with a unique type of mutation, never described in cancers so far, on the tail of histone H3 variants. The most common other alterations comprise PI3K/mTOR pathway alterations, TP53 and ACVR1 mutations and PDGFRA mutations/amplifications.

DIPG infiltrate largely the brainstem before causing any symptom, suggesting that they have a specific way to interact with brain tissue microenvironment, and disseminate through the whole brain and spine as it can be observed at late stages of the disease. Our preliminary data indicate that the different ways to infiltrate are linked with the underlying biological alterations of tumoral cells. To elucidate the complex interactions between tumoral cells and surrounded brain tissue, the specific aims of the project will be: 1) to build relevant in vitro models (Glioma Stem Cell lines, co-cultures with stromal cells) and in vivo models (xenografts or syngenic mouse models), 2) to study tumoral invasion in these animal models using high-field MRI and histology, and compare obtained data with existing data in human DIPG, 3) to unravel the underlying biology associated with this phenomenon both at the tumoral cell level and at the stromal cell level. The research outcomes of this project will help us to understand the specific biology of these tumors, to identify potential therapeutic targets and to develop specific tumor models dedicated to preclinical drug testing in the future.