Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after 177Lu[Lu]-octreotate therapy

Abstract

Introduction: Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with ¹⁷⁷Lu[Lu]-octreotate. Despite being highly effective in animal models, ¹⁷⁷Lu[Lu]-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for ¹⁷⁷Lu[Lu]-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice.

Methods: GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq ¹⁷⁷Lu[Lu]-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed.

Results: Distribution of differentially expressed transcripts indicated a time-dependent treatment response in GOT1 tumors after ¹⁷⁷Lu[Lu]-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively.

Conclusion: Transcriptional analysis showed radiation-induced apoptosis as an early response after ¹⁷⁷Lu[Lu]-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents.

Keywords: (177)Lu-DOTATATE; GEPNET; Midgut carcinoid; Radiation biology; Radiogenomics; Radionuclide therapy.