Comparison of 177Lu-octreotate and 177Lu-octreotide for treatment in human neuroblastoma-bearing mice

A Romiani; K Simonsson; D Pettersson; A Al-Awar; N Rassol; H Bakr; D E Lind; G Umapathy; J Spetz; R H Palmer; B Hallberg; K Helou; E Forssell-Aronsson

doi:10.1016/j.heliyon.2024.e31409

Comparison of ¹⁷⁷Lu-octreotate and ¹⁷⁷Lu-octreotide for treatment in human neuroblastoma-bearing mice

Heliyon. 2024 May 18;10(10):e31409. doi: 10.1016/j.heliyon.2024.e31409. eCollection 2024 May 30.

Authors

A Romiani^{1

2}, K Simonsson^{1

2}, D Pettersson^{1

2}, A Al-Awar^{1

2}, N Rassol^{1

2}, H Bakr^{1

2

3}, D E Lind^{2

4}, G Umapathy^{2

4}, J Spetz^{1

2}, R H Palmer^{2

4}, B Hallberg^{2

4}, K Helou^{2

5}, E Forssell-Aronsson^{1

2

3}

Affiliations

¹ Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁴ Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Abstract

Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of ¹⁷⁷Lu-octreotate and ¹⁷⁷Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes.

Methods: The biodistribution of ¹⁷⁷Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of ¹⁷⁷Lu-octreotate or ¹⁷⁷Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR.

Results: The activity concentration was generally lower in most tissues for ¹⁷⁷Lu-octreotide compared to ¹⁷⁷Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for ¹⁷⁷Lu-octreotide and 2.9 and 0.45 Gy/MBq for ¹⁷⁷Lu-octreotate, respectively. ¹⁷⁷Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with ¹⁷⁷Lu-octreotate. Treatment with ¹⁷⁷Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF.

Conclusion: ¹⁷⁷Lu-octreotide gave somewhat better anti-tumor effects than ¹⁷⁷Lu-octreotate. The similar effect observed in the treated groups with ¹⁷⁷Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.

Keywords: Apoptosis; High-risk neuroblastoma; Lutathera; Radionuclide therapy; Somatostatin analogs.