Characterization and analysis of in vivo intracranial models for glioblastoma
Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. In spite of maximal therapy consisting of surgery, radiotherapy and chemotherapy, GBM remains largely incurable with a median overall survival of less than 15 months. GBM is commonly characterized by complex chromosomal aberrations, while exhibiting a moderate mutational burden compared to other cancer types, all of which target a multitude of pathways. Also, the patho-biology of GBM is further complicated by an extensive inter- and intratumoral heterogeneity with a large variety of genomically and transcriptionally diverging phenotypes, thereby complicating the matching of therapies to particular patient populations. Pathologically, GBM is characterized as a highly infiltrative tumor that shows significant heterogeneity with regard to the expression of astrocytic and neural/cancer stem cell features. In addition, it is considered as a T cells ‘cold’ tumor, with low numbers of tumor infiltrating T cells (TILs), which, when able to infiltrate the tumor, commonly exhibit a terminally exhausted phenotype. On the other hand, GBM tumors enrich for regulatory T-cells, while the most abundant immunologic cell type belongs to the myeloid lineage with anti-inflammatory polarization. The extended immunosuppressive nature of GBM is considered as multifactorial with a multitude of tumor and TME derived factors that prohibit the execution of an effective immune response.
To study therapeutic options for GBM, mouse models that recapitulate the molecular and histological characteristics of glioblastoma are highly required. These commonly include patient-derived xenografts (PDX), which are highly instrumental to study tumor intrinsic features, and syngeneic mouse models of GBM to study the interaction of the tumor and its microenvironment, including cells of the inflammatory system. While protocols to develop PDX models are well established, the currently available syngeneic mouse models only partially recapitulate a small subset of human GBM. In this project, I will develop novel syngeneic mouse models of GBM by intracranially introducing a variety a oncogene combinations typically found in GBM, characterize these models thoroughly (genetically and histologically), and use them to test novel immunotherapeutic approaches in combination with the current standard of care.