Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats

Johannes Zellmer; Hsi-Yu Yen; Lena Kaiser; Erik Mille; Franz Josef Gildehaus; Guido Böning; Katja Steiger; Marcus Hacker; Peter Bartenstein; Andrei Todica; Alexander R Haug; Harun Ilhan

doi:10.1186/s13550-020-00628-y

Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE in Lewis rats

EJNMMI Res. 2020 Apr 25;10(1):41. doi: 10.1186/s13550-020-00628-y.

Authors

Johannes Zellmer¹, Hsi-Yu Yen^{2

3

4}, Lena Kaiser¹, Erik Mille¹, Franz Josef Gildehaus¹, Guido Böning¹, Katja Steiger^{2

4}, Marcus Hacker⁵, Peter Bartenstein¹, Andrei Todica¹, Alexander R Haug⁵, Harun Ilhan⁶

Affiliations

¹ Department of Nuclear Medicine, University Hospital, Ludwig-Maxilimians-University Munich, Munich, Germany.
² Department of Pathology, Technical University of Munich, Munich, Germany.
³ German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany.
⁴ Comparative Experimental Pathology, Technical University of Munich, Munich, Germany.
⁵ Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
⁶ Department of Nuclear Medicine, University Hospital, Ludwig-Maxilimians-University Munich, Munich, Germany. [email protected].

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTA⁰,TYR³-octreotate ([¹⁷⁷Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [¹⁷⁷Lu]Lu-DOTA-TATE in female Lewis rats.

Methods: Animals received 200 MBq of [¹⁷⁷Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [¹⁷⁷Lu]Lu-DOTA-TATE; group 4, everolimus + [¹⁷⁷Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [^99mTc]Tc-mercaptoacetyltriglycine ([^99mTc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS).

Results: Rats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [¹⁷⁷Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [^99mTc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups.

Conclusion: Renal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE.

Keywords: Everolimus; PRRT; Renal clearance; Scintigraphy; [177Lu]Lu-DOTA-TATE.