Pasireotide therapy of multiple endocrine neoplasia type 1-associated neuroendocrine tumors in female mice deleted for an men1 allele improves survival and reduces tumor progression

Abstract

Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1mice were treated from age 12 mo with 40 mg/kg pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1 mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. PasireotidetreatedMen1 micehadincreased survival (pasireotide,80.9%vs PBS, 65.2%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803±0.058 mm3 vs 2.872±0.728 mm3 [pasireotide] compared with 0.844±0.066 mm3 vs 8.847±1.948 mm3 [PBS]; P < .01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36±0.25 vs 3.72±0.32, respectively; <0001) and pituitary NETs (pasireotide, 0.73±0.07% vs PBS, 1.81±0.15%; P>l.0001), but increased apoptosis in pancreatic NETs (pasireotide, 0.42±0.05% vs PBS, 0.19±0.03%; P> .001) and pituitary NETs (pasireotide, 14.75±1.58% vs PBS, 2.35± 0.44%; P > 001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy.