[177Lu]Lu-RM26 radionuclide therapy inhibits glioblastoma growth and extends survival via GRPR targeting
Background
Despite advances, Glioblastoma multiforme (GBM) remains an aggressive brain malignancy with a dismal prognosis. Current standard-of-care therapies often fail due to poor tumor penetration and off-target toxicity, especially given the challenges of the blood-brain barrier. The gastrin-releasing peptide receptor (GRPR) is frequently overexpressed in gliomas, presenting a promising target for localized therapy. Exploiting this overexpression could enable targeted delivery, circumventing systemic limitations and improving therapeutic efficacy.
Study Design
Researchers evaluated [177Lu]Lu-RM26, a lutetium-177-labeled GRPR-targeting antagonist, in an orthotopic GL261Fluc+ glioblastoma mouse model. The compound was administered intratumorally via convection-enhanced delivery. Pharmacokinetic characteristics, including tumor retention and biodistribution, were assessed using serial single-photon emission computed tomography and gamma-counting. Efficacy was determined by tumor volume, bioluminescence signal, and overall survival. Safety was monitored through body weight, neurological scoring, rotarod testing, hematology, and immunohistochemical staining. Mechanistic insights were gained via bulk RNA-sequencing and Western blotting.
Results
Analysis of Chinese Glioma Genome Atlas data showed higher GRPR expression correlated with poorer-prognosis glioma subtypes and reduced survival. In vitro, [177Lu]Lu-RM26 demonstrated dose-dependent inhibition of GL261Fluc+ cell viability, proliferation, and invasion. Locoregional administration of [177Lu]Lu-RM26 led to prolonged tumor retention, measured at 74.7 h, and a high absorbed dose of 2.71 × 106 mGy·MBq- 1, with minimal off-target uptake. Treated mice exhibited marked tumor growth inhibition, a significant reduction in bioluminescence signal, and extended survival compared to controls. Importantly, no significant short-term systemic toxicity or neurological impairment was observed. > Transcriptome and Western blotting analyses confirmed that the therapeutic effects were consistent with DNA replication stalling and G2/M arrest, indicating a clear mechanism of action.
Key Findings
- Higher
GRPRexpression correlated with poorer-prognosis glioma subtypes and reduced survival. [177Lu]Lu-RM26inhibited GL261Fluc+ cell viability, proliferation, and invasion dose-dependently in vitro.- Intratumoral
[177Lu]Lu-RM26achieved prolonged tumor retention (74.7 h) and a high absorbed dose (2.71 × 106 mGy·MBq- 1). - Treated mice showed marked glioblastoma growth inhibition, reduced
bioluminescence, and extended survival. - No significant short-term systemic toxicity or neurological impairment was observed with
[177Lu]Lu-RM26.
Why It Matters
This study highlights the potential of locoregional radionuclide therapy to overcome the limitations of systemic delivery in glioblastoma, a notoriously difficult-to-treat cancer. By directly targeting GRPR-overexpressing tumors with [177Lu]Lu-RM26 via convection-enhanced delivery, it's possible to achieve high local drug concentrations and sustained tumor exposure while minimizing systemic toxicity. This approach could lead to more effective treatment protocols for GBM patients, potentially improving survival and quality of life. While still preclinical, the robust efficacy and favorable safety profile observed suggest a promising path toward clinical translation, particularly for localized or recurrent tumors where direct delivery is feasible.
glioblastoma
grpr
radionuclide-therapy
lu-177
rm26
brain-cancer