Transcriptomic profiling of human GOT1 and GOT2 tumor xenografts in Balb/c nude mice following 177Lu irradiation and/or Sonidegib treatment

The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human small intestine neuroendocrine tumor cell line GOT1 and Medullary thyroid carcinoma model GOT2 have shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In vitro and preclinical in vivo studies have shown that irradiation can up-regulate the expression of somatostatin receptors and thereby give an increased uptake of 177Lu-octreotate. The cellular processes that underlie positive treatment response to 177Lu-octreotate are otherwise largely unknown. Genome-wide analysis of tumor cell responses in this successful mouse model offers a venue to identify critical treatment parameters and to optimize clinical effectiveness of 177Lu-octreotate therapy. Combining 177Lu-octreotate with other anti-tumor agents has also been proposed as a strategy for optimization. Some studies have shown synergistic effects in tumor cell killing and volume reduction The hedgehog signaling pathway is involved in embryonic development and tissue regeneration and can be/is abnormally activated in various cancers. Inhibition of the hedgehog signaling pathway has yielded promising therapeutic effects on NE tumors and may potentially enhance the effects of 177Lu-octreotate treatment in patients. Tumor-bearing BALB/c nude mice were i.v. injected with 5, 7, 10, 15 or 30 MBq 177Lu-octreotate. The groups receiving 5 and 10 MBq 177Lu-octreotate were given an additional 10 or 5 MBq 177Lu-octreotate 24 h after the first injection, respectively. One group was given Sonidegib (80 mg/kg twice a week via oral gavage), and one group was given Sonidegib together with 30 MBq 177Lu-octreotate. Control animals were injected with NaCl. Animals were killed after 1, 3, 7 or 41 days for the 5+10, 10+5 and 15 MBq treatments, after 24 hours for the 7 MBq treatment, and after 41 days for the 30 MBq treatment. Tumor samples were excised and snap frozen in liquid nitrogen, followed by total RNA extraction.