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- Berglund, Hanna, et al.
(författare)
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p53 stabilisation potentiates [177Lu]Lu-DOTATATE treatment in neuroblastoma xenografts
- 2023
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089.
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Tidskriftsartikel (refereegranskat)abstract
- PurposeMolecular 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.MethodsThis 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.ResultsThe 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.ConclusionIn 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.
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- Fortin, Marc-André, et al.
(författare)
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Immuno-PET of undifferentiated thyroid carcinoma with radioiodine-labelled antibody cMAb U36 : application to antibody tumour uptake studies
- 2007
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 34:9, s. 1376-1387
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We tested the suitability of the chimeric monoclonal anti-human CD44 splice version 6 antibody (cMAb U36) for targeting and visualising human anaplastic thyroid carcinoma with PET. We also performed experiments aimed at elucidating the relation between tumour interstitial fluid pressure (TIFP) and the tumour uptake of antibodies. METHODS: The affinity and specificity of the cMAb U36 for KAT-4 cells were evaluated in vitro, as was the Na+/I- symporter (NIS) expression. Biodistribution studies were performed on KAT-4 carcinoma-bearing mice injected with 124I-cMAb U36 or free iodine. Biodistribution studies were also performed in animals treated with the specific TGF-beta1 and -beta3 inhibitor Fc:TbetaRII, which lowers TIFP. Treated and non-treated animals were scanned by microPET. RESULTS: Cultured human undifferentiated/anaplastic thyroid carcinoma KAT-4 cells expressed low levels of NIS and uptake of free iodine was insignificant. The cMAb U36 expressed an affinity (KD) of 11+/-2 nM. Tumour radioactivity uptake reached maximum values 48 h after injection of 124I-cMAb U36 (approximately 22%IA/g). KAT-4 carcinomas were readily identified in all 124I-immuno-PET images. Radioactivity tumour uptake in Fc:TbetaRII-treated animals was significantly lower at 24 and 48 h after injection, and five times higher thyroid uptake was also noted. CONCLUSION: We successfully used 124I-cMAb U36 to visualise CD44v6-expressing human anaplastic thyroid carcinoma. Given the lack of NIS expression in KAT-4, tumour visualisation is not due to free iodine uptake. Lowering the TIFP in KAT-4 carcinomas did not increase the uptake of mAbs into tumour tissue.
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| 6. |
- Lundsten, Sara, et al.
(författare)
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The radiosensitizer Onalespib increases complete remission in Lu-177-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
- 2020
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 47:4, s. 980-990
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Lu-177-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of Lu-177-DOTATATE. Consequently, the aim of this study was to assess the potential of Onalespib in combination with Lu-177-DOTATATE in vivo and to examine the toxicity profiles of the treatments.Methods: Lu-177-DOTATATE selectivity and distribution in NET xenografts were studied using biodistribution and autoradiography. Therapeutic effects of Onalespib in combination with Lu-177-DOTATATE were studied in NET xenografts. Histological analyses were used to assess molecular effects from treatment and to establish toxicity profiles.Results: Biodistribution and autoradiography confirmed the SSTR-selective tumor uptake of Lu-177-DOTATATE, which was unaffected by Onalespib treatment. Immunohistochemistry verified molecular responses to Onalespib therapy in the tumors. While Onalespib and Lu-177-DOTATATE monotherapies resulted in a 10% and 33% delay in tumor doubling time compared with control, the combination treatment resulted in a 73% delayed tumor doubling time. Moreover, combination treatment increased complete remissions threefold from Lu-177-DOTATATE monotherapy, resulting in 29% complete remissions. In addition, histological analyses demonstrated radiation-induced glomerular injury in the Lu-177-DOTATATE monotherapy group. The damage was decreased tenfold in the combination group, potentially due to Onalespib-induced HSP70 upregulation in the kidneys.Conclusion: Treatment with Onalespib potentiated Lu-177-DOTATATE therapy of NET xenografts with a favorable toxicity profile. Utilizing Onalespib's radiosensitizing properties with Lu-177-DOTATATE may lead to better therapeutic results in the future and may reduce unwanted side effects in dose-limiting organs.
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