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

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). Men1(+/-) mice 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. Pasireotidetreated Men1(+/-) mice had increased survival (pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 +/- 0.058 mm(3) vs 2.872 +/- 0.728 mm(3) [pasireotide] compared with 0.844 +/- 0.066 mm(3) vs 8.847 +/- 1.948 mm(3) [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; P < .001), with decreased proliferation in pancreatic NETs (pasireotide, 0.35 +/- 0.03% vs PBS, 0.78 +/- 0.08%; P < .0001) and pituitary NETs (pasireotide, 0.73 +/- 0.07% vs PBS, 1.81 +/- 0.15%; P < .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.