Studies on a combined therapy of photon irradiation and radioligand therapies with 177Lutetium and 225Actinium-labeled FAP tracers in an orthotopic glioblastoma mouse model

• Applicants: Professor Dr. Peter Ernst Huber; Privatdozent Dr. Manuel Röhrich
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565701213

Despite substantial advances in cancer treatment, glioblastoma (GBM) still has a bleak prognosis, with a median overall survival of approximately 15 months and a 5-year survival rate below 8%. Radiotherapy remains a cornerstone in the management of GBM, primarily by inducing DNA double-strand breaks and oxidative stress that lead to cellular apoptosis or cell cycle arrest. However, its effectiveness is often compromised by dosage limitations and the highly complex genetic, molecular and cellular mechanisms involved. Fibroblast activation protein (FAP) is overexpressed in various solid tumors and confers to tumor progession in suppressing antitumor immunity, promoting tumor growth, and driving epithelial–mesenchymal transition (EMT), making it a significant prognostic marker in numerous malignancies including high grade gliomas. Targeting FAP represents a promising avenue for improving treatment efficacy of GBM. Although the characteristics and mechanistic functions of the FAP-positive cells in GBM are not fully understood, upregulated FAP expression is notably observed in GBM, both in tumor cells and stromal components, such as mesenchymal cells, endothelial cells and pericytes. Combining FAP-targeted radioligand therapy (RLT) with Lutetium or Actinium-labeled FAP-specific tracers with external photon radiation thus may emerge as a promising strategy for treatment of GBM. External photon radiation targets larger tumor masses, while FAP-targeted RLT can address multiple tumor lesions at different sites or regions resistant to external photon radiation. In the planned project, we intend to characterize the mechanistic effects of photon irradiation and FAP-targeted RLT (mono- and combined therapies) in vitro and in an orthotopic GBM mouse model. Our aim is to investigate this novel combinatorial therapeutic approach and its underlying mechanisms preclinically to provide a rationale of its clinical translation in glioblastoma.

• DFG Programme: Research Grants