Background: Glioblastoma (GBM) - the most frequent and aggressive brain tumor - treatment has not changed in the last 25 years. All clinical trials have failed, mostly because of the limited penetration of the drugs through the blood-brain barrier (BBB) and their poor distribution in the heterogeneous GBM tissue. Strategies to selectively open the BBB and the use of nanoparticles (NPs) improving the drug penetration into tumors and malignant cells, have been proposed, although they have not arrived to clinical trials yet.
Hypothesis and aims: We hypothesize that the combination of BBB opening approaches with drug loaded and tumor-targeted NPs can improve the treatment of GBM patients. To prove this thesis, two leads will be followed:
1) SNGR-TNF, a potent and stable derivative of NGR-TNF molecule with the ability to permeate the BBB and already validated in brain lymphomas, will be tested in combination with temozolomide.
2) We will design, synthesize and characterize NPs loaded with highly active anti-GBM drugs and functionalized with specific peptides to improve tumor penetration and access to cancer stem cells. Finally, the most promising NPs will be then tested in combination with SNGR-TNF.
Methods: Candidate nanomedicines will be screened in state-of-the-art in vitro GBM models developed by our experts in GBM biology. In vivo experimental therapy studies using SNGR-TNF and nanomedicines will be carried out on clinically relevant GBM mouse models and spontaneous canine gliomas. Our experts in photonics will analyze the distribution of nanocarriers and drugs in cells and tumors.
Potential impact: ReachGLIO will provide the pre-clinical framework needed to develop a novel and effective therapy for GBM based on NP loaded with potent anti-GBM drugs, alone or in combination with SNGR-TNF. This work will attract future investments needed to conduct Investigational New Drug-enabling studies and, eventually, GBM clinical trials.