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Combination treatments to enhance peptide receptor radionuclide therapy of neuroendocrine tumours

European Journal of Nuclear Medicine and Molecular Imaging volume 47, pages 907–921 (2020)Cite this article

Abstract

The incidence of neuroendocrine tumours (NETs) is increasing, but curative therapeutic options are limited because diagnosis is often delayed until the tumour has metastasized. Peptide receptor radionuclide therapy (PRRT) is among the most effective therapeutic options for metastatic NETs because of targeted delivery of radioactivity to the tumour via the somatostatin receptor (SSTR) and relatively low systemic toxicity. However, current PRRT regimes result in palliation rather than cure, and higher doses of PRRT that might achieve remission would also be too toxic to the patients. Therefore, there is a need to improve PRRT of NETs by combining it with other agents to achieve maximum benefits from the internal radiation therapy, while sparing non-target organs from radiation toxicity. Here we review various current and potential combination strategies to improve 177Lu-octreotate-based PRRT of NET, some of which could also apply to other radionuclide therapies. These strategies include co-administered drugs that improve delivery of the radiopharmaceutical via increased tumour perfusion or through increased SSTR density at tumour surface. Other combinations are aimed at enhancing the biological effects of the radiation-induced DNA damage in tumour cells or generating additional DNA damage burden to effectively increase the cytotoxicity of PRRT. We also propose an algorithm for stratifying NET patients to receive or not combination therapies with PRRT. Considering that PRRT and many of these combination agents are already used for treating patients with NET and other cancers, the proposed strategies to improve the efficacy of PRRT could be rapidly translated into the clinic.

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Acknowledgments

We would like to thank Marine A. Merlin for helpful discussion to improve the manuscript.

Funding

This work was supported by research funding to J.M.B. and G.M.S. from the Canadian Cancer Society Research Institute (grant no. 705327) and the Carcinoid-NeuroEndocrine Tumor Society of Canada,; and to J.M.B. from the Education and Research Foundation for Nuclear Medicine and Molecular Imaging, Quebec Bio-Imaging Network, Fondation du CHU de Québec – Université Laval and Fonds de Recherche du Québec – Santé. S.A. received a scholarship from the Canadian Institutes of Health Research.

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  1. Department of Radiology and Nuclear Medicine and Cancer Research Centre, Université Laval, Quebec City, QC, Canada

    Samuel Adant & Jean-Mathieu Beauregard

  2. Department of Medical Imaging and Oncology Division of Research Centre, CHU de Québec – Université Laval, 11, Côte du Palais, Quebec City, G1R 2J6, QC, Canada

    Samuel Adant & Jean-Mathieu Beauregard

  3. Department of Molecular Biology, Medical Biochemistry and Pathology and Cancer Research Centre, Université Laval, Quebec City, QC, Canada

    Samuel Adant & Girish M. Shah

  4. Neurosciences and Oncology Divisions of CHU de Québec – Université Laval Research Centre, Quebec City, QC, Canada

    Samuel Adant & Girish M. Shah

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  1. Samuel Adant
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Correspondence to Girish M. Shah or Jean-Mathieu Beauregard.

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Adant, S., Shah, G.M. & Beauregard, JM. Combination treatments to enhance peptide receptor radionuclide therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging 47, 907–921 (2020). https://doi.org/10.1007/s00259-019-04499-x

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Keywords

  • Neuroendocrine tumours
  • Peptide receptor radionuclide therapy
  • 177Lu-octreotate
  • 177Lu-DOTATATE
  • Somatostatin receptor
  • Radiosensitization
  • Receptor upregulation
  • Tumour perfusion
  • DNA damage