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The radiosensitizer...
The radiosensitizer Onalespib increases complete remission in Lu-177-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
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- Lundsten, Sara (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Spiegelberg, Diana, 1982- (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Plastikkirurgi
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- Raval, Nakul (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Nestor, Marika, 1976- (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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(creator_code:org_t)
- 2020-01-07
- 2020
- Engelska.
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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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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Neuroendocrine cancer
- Lu-177-DOTATATE
- HSP90
- Onalespib
- Radiosensitization
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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