Combination of Peptide Receptor Radionuclide Therapy with Lu-177 DOTATATE and the m-TOR inhibitor RAD001 (Everolimus) in AR42J tumor bearing mice and response assessment by Ga-68 DOTATATE PET

1346b Aim: The m-TOR inhibitor RAD001 (Everolimus) and Peptide Receptor Radionuclide Therapy (PRRT) with the beta-emitter Lu-177 DOTATATE are both approved in the treatment of metastasized neuroendocrine tumors (NET). As these therapy options target tumor cells on different pathways, a combined therapy might be associated with better response. The aim of the current preclinical study was to evaluate the efficacy of a combined treatment with the m-TOR inhibitor and with Lu-177 DOTATATE in a somatostatin-receptor (SSTR) positive tumor model of the mouse. Methods: 10 week old athymic CD1-mice were injected with the SSTR-positive AR42J tumor cell line at day 0 and divided into 4 therapy groups (Gr.). Gr. 1 (n=7) received a placebo, Gr. 2 (n=8) 5 mg/kg RAD001 weekly, Gr. 3 (n=7) a single PRRT cycle with 80 MBq Lu-177 DOTATATE and Gr. 4 (n=8) a combination of a single PRRT cycle and 5 mg/kg RAD001 weekly. The therapy was started following a baseline Ga-68 DOTATATE PET at day 5. Follow-up Ga-68 DOTATATE PET was performed 1, 2 and 4 weeks after. Therapy response was assessed by monitoring the tumor growth with manual measurement of tumor volumes (manual tumor volume, MTV) and threshold based ROI-measurements in Ga-68 DOTATATE PET (biological tumor volume, BTV). Tracer Uptake in PET was measured semi-quantitatively as a tumor to reference ratio (TRR; maximum uptake in the tumor divided by mean uptake in muscle as reference). Numbers are given as mean ±SEM. Results: Excessive tumor growth 2 weeks after start of therapy lead to an early euthanasia of mice treated with placebo and RAD001 monotherapy according to the regulations of the local animal ethics committee. One animal of Gr. 4 (combined PRRT and RAD001) was lost due to aspiration during the application of RAD001 at day 26. The remaining animals of Gr. 3 and 4 had to be euthanized after the last PET scan 4 weeks after start of treatment. There was a high correlation of manually assessed MTV and PET-based BTV (r²=0.9). Tumor growth and volume was significantly (p