Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale
<sup>177</sup>Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells...
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2021
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oai:doaj.org-article:a9754249b27b4e299cd42ae821706fd72021-11-25T16:49:06ZOptimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale10.3390/biomedicines91115702227-9059https://doaj.org/article/a9754249b27b4e299cd42ae821706fd72021-10-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1570https://doaj.org/toc/2227-9059<sup>177</sup>Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair <sup>177</sup>Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (<i>TNED</i>). The aim of this study was to investigate how to enhance <sup>177</sup>Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with <sup>177</sup>Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during <sup>177</sup>Lu-DOTATATE treatment, the concept of relative biological effectiveness (<i>RBE</i>) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of <sup>177</sup>Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an <i>RBE</i> value of 2 for both the tumour and normal tissues, the <i>TNED</i> was increased compared to <sup>177</sup>Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of <sup>177</sup>Lu-DOTATATE treatment and be continued for up to four weeks to optimize the <i>TNED</i>. Based on these results, a phase I trial assessing the combination of olaparib and <sup>177</sup>Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).Andreas HallqvistJohanna SvenssonLinn HagmarkerIda MarinTobias RydénJean-Mathieu BeauregardPeter BernhardtMDPI AGarticle<sup>177</sup>Lu-DOTATATEPARP inhibitorsomatostatin positive tumorolaparibBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1570, p 1570 (2021) |
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| topic |
<sup>177</sup>Lu-DOTATATE PARP inhibitor somatostatin positive tumor olaparib Biology (General) QH301-705.5 |
| spellingShingle |
<sup>177</sup>Lu-DOTATATE PARP inhibitor somatostatin positive tumor olaparib Biology (General) QH301-705.5 Andreas Hallqvist Johanna Svensson Linn Hagmarker Ida Marin Tobias Rydén Jean-Mathieu Beauregard Peter Bernhardt Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale |
| description |
<sup>177</sup>Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair <sup>177</sup>Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (<i>TNED</i>). The aim of this study was to investigate how to enhance <sup>177</sup>Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with <sup>177</sup>Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during <sup>177</sup>Lu-DOTATATE treatment, the concept of relative biological effectiveness (<i>RBE</i>) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of <sup>177</sup>Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an <i>RBE</i> value of 2 for both the tumour and normal tissues, the <i>TNED</i> was increased compared to <sup>177</sup>Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of <sup>177</sup>Lu-DOTATATE treatment and be continued for up to four weeks to optimize the <i>TNED</i>. Based on these results, a phase I trial assessing the combination of olaparib and <sup>177</sup>Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267). |
| format |
article |
| author |
Andreas Hallqvist Johanna Svensson Linn Hagmarker Ida Marin Tobias Rydén Jean-Mathieu Beauregard Peter Bernhardt |
| author_facet |
Andreas Hallqvist Johanna Svensson Linn Hagmarker Ida Marin Tobias Rydén Jean-Mathieu Beauregard Peter Bernhardt |
| author_sort |
Andreas Hallqvist |
| title |
Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale |
| title_short |
Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale |
| title_full |
Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale |
| title_fullStr |
Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale |
| title_full_unstemmed |
Optimizing the Schedule of PARP Inhibitors in Combination with <sup>177</sup>Lu-DOTATATE: A Dosimetry Rationale |
| title_sort |
optimizing the schedule of parp inhibitors in combination with <sup>177</sup>lu-dotatate: a dosimetry rationale |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/a9754249b27b4e299cd42ae821706fd7 |
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