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Optimization of combined temozolomide and peptide receptor radionuclide therapy (PRRT) in mice after multimodality
Sander M Bison1,2, Joost C Haeck3,4, K Bol5,6
1Department of Nuclear Medicine, Erasmus MC, Postbus 2040, Rotterdam, 3000, CA, The Netherlands. s.bison@eramusmc.nl.
Background:
Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate ((177)Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ.
Methods:
We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq (177)Lu-TATE or TMZ (oral 50 mg/kg daily for 14 days). Tumour perfusion was evaluated weekly by dynamic contrast-enhanced MRI (DCE-MRI), whereas tumour uptake of (111)In-octreotide was quantified using SPECT/CT until day 39 after treatment. Based on these results, seven different (177)Lu-octreotate and TMZ combination schemes were evaluated for therapy response, varying the order and time interval of the two therapies and compared with single treatments.
Results:
PRRT and TMZ both resulted in tumour size reduction, accompanied by significant changes in MRI characteristics such as an enhanced tumour perfusion. Moreover, TMZ treatment also resulted in increased uptake of the SST analogue (111)In-octreotide until day 13. In the subsequent therapy study, 90 % of animals receiving (177)Lu-TATE at day 14 after TMZ treatment showed complete response, being the best anti-tumour results among groups.
Conclusions:
Molecular imaging studies indicated that PRRT after TMZ treatment could induce optimal therapeutic effects because of enhanced tumour uptake of radioactivity after TMZ, which was confirmed by therapy responses. Therefore, clinical translation of TMZ treatment prior to PRRT might increase tumour responses in NET patients as well.
Insights
Combining peptide receptor radionuclide therapy (PRRT) with temozolomide (TMZ) shows promise for neuroendocrine tumors (NET). Administering PRRT after TMZ enhances therapeutic effects and tumor uptake of radioactivity, suggesting a potential new clinical treatment strategy.
Area of Science:
- Oncology
- Nuclear Medicine
- Radiopharmacology
Background:
- Neuroendocrine tumors (NET) overexpressing somatostatin receptors (SSTR) are treated with peptide receptor radionuclide therapy (PRRT) using lutetium-177-labelled octreotate ((177)Lu-TATE) or temozolomide (TMZ).
- Combination therapy may yield additive effects, necessitating investigation into optimal administration schedules.
Purpose of the Study:
- To evaluate tumor characteristics and therapeutic responses to combined PRRT and TMZ using molecular imaging in a murine model.
- To identify the optimal treatment schedule for PRRT plus TMZ in SSTR-overexpressing NET.
Main Methods:
- Molecular imaging studies in mice with SSTR-expressing H69 tumors after single administration of (177)Lu-TATE or TMZ.
- Tumor perfusion assessed via dynamic contrast-enhanced MRI (DCE-MRI); (111)In-octreotide uptake quantified using SPECT/CT.
- Seven combination schemes of (177)Lu-octreotate and TMZ were evaluated, varying order and timing.
Main Results:
- Both PRRT and TMZ reduced tumor size and enhanced tumor perfusion.
- TMZ treatment increased (111)In-octreotide uptake until day 13.
- Complete tumor response (90% of animals) was observed with (177)Lu-TATE administered 14 days after TMZ, showing the best anti-tumor outcome.
Conclusions:
- Molecular imaging suggests PRRT following TMZ treatment optimizes therapeutic effects due to enhanced tumor radioactivity uptake.
- This combined approach, with TMZ preceding PRRT, holds potential for increased tumor response in NET patients.
- Clinical translation of TMZ prior to PRRT may improve outcomes for NET patients.
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