[161Tb]Tb-AMTG significantly extends survival in prostate cancer mice, outperforming [177Lu]Lu-RM2 and [177Lu]Lu-AMTG
Background
Prostate cancer remains a significant health challenge, with advanced stages often requiring innovative therapeutic approaches. Radioligand therapy (RLT) offers targeted treatment, but optimizing radionuclide selection is crucial. While 177Lu is an established therapeutic radionuclide, 161Tb is gaining interest due to its additional emission of high-energy Auger and conversion electrons, which can enhance localized cell damage. This study investigates if combining 161Tb with the gastrin-releasing peptide receptor (GRPR) antagonist AMTG, known for superior in vivo stability, could improve treatment efficacy over 177Lu and the less stable RM2.
Study Design
Treatment studies were conducted in PC-3 tumor-bearing Nu/J mice, initiating therapy when tumor volumes reached ~100 mm3. 161Tb- and 177Lu-labeling of GRPR antagonists RM2 and AMTG was performed at 90 °C for 10 min (molar activity ~50 MBq/nmol). Treatment groups (n=6-7 per group) received ~15 MBq of the radiolabeled compound on day 0 and day 7. Control animals received vehicle. Primary endpoints included tumor control and overall survival, with animals sacrificed when tumor volume exceeded 1,500 mm3. Toxicity was assessed in healthy animals (n=3 per group) via complete blood count and metabolic panel 45 days post-injection.
Results
All radiolabeled treatments, including [177Lu]Lu-RM2, [177Lu]Lu-AMTG, [161Tb]Tb-RM2, and [161Tb]Tb-AMTG, significantly improved tumor control and overall survival compared to vehicle controls. Each treatment group received a total activity of 26-31 MBq. The combination of 161Tb with the more stable AMTG demonstrated superior efficacy.
[161Tb]Tb-AMTGachieved the longest median overall survival of 58.1 ± 5.4 days after treatment initiation, indicating a substantial therapeutic advantage. This result supports the hypothesis that the synergistic effect of161Tb's Auger electron emission andAMTG's enhanced in vivo stability leads to improved tumor response. Importantly, no signs of long-term toxicity were observed across any treatment group, suggesting a favorable safety profile for these radioligands.
Key Findings
- All
161Tb- and177Lu-labeled GRPR antagonists improved tumor control and overall survival in PC-3 mice. [161Tb]Tb-AMTGachieved the longest median overall survival of 58.1 ± 5.4 days.- The total activity administered per treatment group was 26-31 MBq.
- No long-term toxicity was observed in any treatment group.
- Superior in vivo stability of
AMTGcombined with161Tb's Auger electrons enhanced therapeutic efficacy.
Why It Matters
The combination of 161Tb with the GRPR antagonist AMTG represents a promising advancement for targeted prostate cancer therapy. This study provides strong preclinical evidence that leveraging 161Tb's Auger electron emissions alongside a highly stable peptide like AMTG can significantly enhance tumor control and extend survival without increasing toxicity. For clinicians and researchers, this suggests a potent new radioligand therapy strategy, potentially leading to more effective protocols for patients with advanced prostate cancer. While still in preclinical stages, these findings lay the groundwork for future clinical translation, indicating that optimizing both the radionuclide and the targeting ligand's stability is key to maximizing therapeutic outcomes in radiotheranostics.
prostate cancer
radioligand therapy
161tb
177lu
amtg
rm2