Endocrine Abstracts (2015) 38 P146 | DOI: 10.1530/endoabs.38.P146

The somatostatin analogue pasireotide decreased proliferation and increased apoptosis in pancreatic and pituitary neuroendocrine tumors in a MEN1 mouse model

Mark Stevenson1, Gerard Walls1, Ben Soukup1, Kate Lines1, Ashley Grossman1, Herbert Schmid2 & Rajesh Thakker1

1University of Oxford, Oxford, UK; 2Novartis Pharmaceuticals, Basel, Switzerland.

Improved therapies for pancreatic and pituitary neuroendocrine tumors (NETs), which may occur in Multiple Endocrine Neoplasia type 1 (MEN1), are needed. We assessed the effects of pasireotide, a somatostatin analogue with high affinity for somatostatin receptors (SSTRs) −1, −2, −3 and −5, in a mouse model of MEN1. Men1+/− mice treated from 12 months of age with 40 μg/g pasireotide (n=71), or phosphate-buffered saline (PBS) (n=73), i.m. each month for 9 months, had magnetic resonance imaging (MRI) at 12 and 21 months of age, and received oral 5-bromo-2-deoxyuridine (BrdU), to assess tumour development and proliferation respectively. NETs were harvested at 21 months, and proliferation and apoptosis assessed by immunohistochemical quantification of BrdU-stained nuclei and TUNEL assays, respectively. Immunohistochemical analysis confirmed that the pancreatic and pituitary NETs expressed high levels of SSTR1, 2 and 5 and lower levels of SSTR3. Pasireotide-treated Men1+/− mice had increased survival (82% (pasireotide) vs. 64% (PBS), P<0.05), were associated with the development of fewer pancreatic (86% (pasireotide) vs. 98% (PBS)) and pituitary (52% (pasireotide) vs. 72% (PBS)) NETs (both P<0.05), and had smaller increases in pituitary NET volumes (pre-treated vs post-treated =0.870±0.087mm3 vs 3.094±0.714 mm3 (pasireotide) compared to 0.843±0.065mm3 vs 8.847±1.948mm3 (PBS), P<0.01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared to PBS-treated mice (2.36±0.25 vs 3.72±0.32, respectively, P<0.001), had decreased proliferation in pancreatic (0.35±0.03% (pasireotide) vs. 0.78±0.08% (PBS)) and pituitary (0.73±0.07% (pasireotide) vs. 1.81±0.15% (PBS)) NETs (both P<0.0001), but had increased apoptosis in pancreatic (0.42±0.05% (pasireotide) vs. 0.19±0.03% (PBS)) and pituitary (14.75±1.58% (pasireotide) vs. 2.35±0.44% (PBS)) NETs (both P<0.001). Thus in summary, pasireotide treatment increased survival by ~20% and inhibited pancreatic and pituitary NET growth, indicating its potential as an anti-proliferative and pro-apoptotic therapy for pancreatic and pituitary NETs.

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