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p53 stabilisation potentiates [177Lu]Lu-DOTATATE treatment in neuroblastoma xenografts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Ridgeview Instruments AB, SE-752 38, Uppsala, Sweden.ORCID iD: 0000-0002-0063-3233
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.ORCID iD: 0000-0002-7364-5470
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2023 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089Article in journal (Refereed) Epub ahead of print
Abstract [en]

Purpose

Molecular radiotherapy is a treatment modality that is highly suitable for targeting micrometastases and [177Lu]Lu-DOTATATE is currently being explored as a potential novel treatment option for high-risk neuroblastoma. p53 is a key player in the proapoptotic signalling in response to radiation-induced DNA damage and is therefore a potential target for radiosensitisation.

Methods

This study investigated the use of the p53 stabilising peptide VIP116 and [177Lu]Lu-DOTATATE, either alone or in combination, for treatment of neuroblastoma tumour xenografts in mice. Initially, the uptake of [177Lu]Lu-DOTATATE in the tumours was confirmed, and the efficacy of VIP116 as a monotherapy was evaluated. Subsequently, mice with neuroblastoma tumour xenografts were treated with placebo, VIP116, [177Lu]Lu-DOTATATE or a combination of both agents.

Results

The results demonstrated that monotherapy with either VIP116 or [177Lu]Lu-DOTATATE significantly prolonged median survival compared to the placebo group (90 and 96.5 days vs. 50.5 days, respectively). Notably, the combination treatment further improved median survival to over 120 days. Furthermore, the combination group exhibited the highest percentage of complete remission, corresponding to a twofold increase compared to the placebo group. Importantly, none of the treatments induced significant nephrotoxicity. Additionally, the therapies affected various molecular targets involved in critical processes such as apoptosis, hypoxia and angiogenesis.

Conclusion

In conclusion, the combination of VIP116 and [177Lu]Lu-DOTATATE presents a promising novel treatment approach for neuroblastoma. These findings hold potential to advance research efforts towards a potential cure for this vulnerable patient population.

Place, publisher, year, edition, pages
Springer, 2023.
Keywords [en]
Neuroblastoma, Molecular radiotherapy, p53, [177Lu]Lu-DOTATATE, Radiosensitisation
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-517191DOI: 10.1007/s00259-023-06462-3ISI: 001085247400001PubMedID: 37823909OAI: oai:DiVA.org:uu-517191DiVA, id: diva2:1817031
Funder
Swedish Childhood Cancer Foundation, PR2020-0023Swedish Research Council, 2020-01377Swedish Cancer Society, CAN 20 0191Swedish Cancer Society, 2018/494Uppsala UniversitySwedish Childhood Cancer Foundation, TJ2021-0072Ulf Lundahls minnesfond
Note

De två första författarna delar förstaförfattarskapet

Available from: 2023-12-05 Created: 2023-12-05 Last updated: 2023-12-11Bibliographically approved

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Berglund, HannaLundsten Salomonsson, SaraMohajershojai, TabassomLane, David P.Nestor, Marika
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Cancer precision medicineDepartment of Immunology, Genetics and Pathology
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