Investigating glioblastoma vulnerabilities using advanced preclinical models and network-targeted therapies
Glioblastoma (GB) is the most aggressive and common primary malignant brain tumour in adults. Despite surgery, radiotherapy, and chemotherapy, median patient survival remains about 15 months.Tumour-cell infiltration and heterogeneity are key factors underlying the dismal prognosis of GB. The paucity of preclinical models that mimic the genetic and microenvironmental complexity of the disease has limited our understanding of GB biology and development of effective precision medicine approaches.
To overcome these limitations, we took advantage of an autochthonous mesenchymal GB model based on postnatal electroporation of neural stem cells within the mouse brain usingdefined tumour suppressor deletions characterising human mesenchymal GB.
Through detailed phenotypic and molecular characterisation, I aim to define the foundational profiles of tumour cell populations from the tumour bulk and far-infiltration zones. I will then test candidate drugs - including senicapoc, meclofenamate, bio‑indirubin, and perampanel - alone as well as with standard therapy to assess their effects on proliferation, invasion, and survival. These network‑targeting agents aim to disrupt intercellular signalling processes that sustain tumour growth and progression. Furthermore, I will employ organotypic brain slice cultures in order to model tumour‑immune interactions and invasion dynamics in a more physiologically relevant environment.
This integrated system combines autochthonous mouse models, tumour-derived GB lines and advanced 3D cultures to prioritise potential therapeutic targets for in-vivo investigation and ultimately foster new, much-needed translational efforts.