Introduction:
The Glucagon-like-Peptide-1 (GLP-1) receptor is an interesting target in tumor diagnosis and therapy with Exendin-based radiopeptides as it is overexpressed on human insulinomas and gastrinomas. We have recently shown high therapeutic efficacy using a radiopeptide labeled with the Auger-emitter 111 In in a transgenic mouse model developing insulinoma-like tumors originating from pancreatic islet cells. Because of high kidney uptake kidney toxicity was found in the animals. The aim of this work was to study efficacy and kidney toxicity of a combination of the angiogenesis inhibitor PTK 787 with 111 In-Exendin-4.
Experimental: Rip1Tag2 transgenic mice develop insulinoma-like tumors in a reproducible manner. We performed oral treatment with PTK 787 daily for 1 week and studied 4 h-biodistribution using 111 In-Exendin-4 0, 3, 5 and 7 days after the initiation of PTK 787 treatment. To assess the efficacy of combined antiangiogenesis treatment and targeted radionuclide therapy, Rip1Tag2 mice were injected with 1.1 MBq 111 In-Exendin-4 shortly after initiating PTK 787 treatment. After 7 days mice were sacrificed and tumor volume, histology (H&E) and cell proliferation studied. In addition, monotherapies with either 1.1 MBq, 28 MBq 111 In-Exendin-4 or PTK were performed. Long term toxicity was performed in C57BI/6J mice 6 months after combined and monotherapy.
Results and Discussion: Due to high GLP-1 receptor expression in the tumor of Rip1-Tag2 mice, the tumor uptake of the radiopeptide was 210Β±52% IA/g 4h after start of combination therapy with a tumor-to-kidney ratio of 0.7. Five and 7 days after initiating PTK treatment this value decreased to <90% IA/g. Therapy efficacy of combination treatment and different monotherapies is shown in Table 1. Combined therapy shows very similar efficacy as high dose radionuclide therapy. Whereas the latter showed tubular necrosis and glomerular sclerosis 6 months after initiation, the combined therapy did not reveal any differences in the kidney morphology between control and treated mice. Table 1. Tumor volumes 7 days after different therapies Median, mm 3 Control n=11 18.6 (100%) 1.1 MBq n=7 3.7 (20%) PTK n=11 4.6 (25%) 28 MBq n=11 0.83 (4.5%) 1.1 MBq+PTK n=10 0.53 (2.8%)
Conclusion:
The present study indicates that a combination of antiangiogenesis treatment and low dose targeted radionuclide therapy can massively reduce tumor volume (>97%) and cell proliferation of small tumors without any organ toxicity. As VEGF-mediated angiogenesis and GLP-1 receptor density in the Rip1Tag2 mouse tumor model are comparable in human insulinomas, the results might be transferable to human tumors with high GLP-1 receptor density and concomitant VEGF-driven angiogenesis.