Metastasis after mTOR inhibition by RAD001 in a neuroendocrine rat tumor model: Combination therapy with ¹⁷⁷Lu-DOTA,Tyr₃-octreotate

Objectives The mTOR inhibitor RAD001 has shown promising anti-tumor effects against neuroendocrine tumors (NETs) alone or in combination with Octreotide LAR. Another most effective therapy for such tumors is Peptide Receptor Radionuclide Therapy (PRRT) with ¹⁷⁷Lu-DOTA,Tyr₃-octreotate. Therefore, we investigated mTOR inhibition combined with PRRT in a rat model.

Methods 47 rats with sc CA20948 primary tumors were treated as shown below. PRRT was given as single treatment 4 days after start of RAD001. RAD001 was given 2x/week for 4.5 weeks. Tumor size and body weight (bw) were determined 3x/week. Sc tumors > 4000 mm3 were surgically removed without euthanizing the animal.

Results RAD001 treatment showed minor antitumor effect compared to control, whereas combination treatment showed more pronounced antitumor effects. PRRT resulted in an even more pronounced antitumor effect though. In RAD001-only and in the combination treatment groups unexpected loss of BW was detected, caused by metastasized tumor to liver, lungs and lymph nodes (23/31 animals). All animals in the control and PRRT-only groups remained metastasis free, exept for one animal with incomplete surgical removal of the sc tumor.

Conclusions Combining RAD001 with PRRT did not result in an increased antitumor effect compared to PRRT alone. RAD001 treatment and the combination treatment resulted however in the development of distant metastasis, leading to poor survival, whereas PRRT-only and vehicle (control)treatment did not in 15/16 animals. Survival of animals treated with RAD001-only or in combination with PRRT was significantly lower compared to control and PRRT-only animals (p≤0.05, log-rank test, Bonferroni corrected)

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