title: 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). 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. Pasireotide-treated 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.
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Gerard V
authors.initials: GV
authors.lastname: Walls
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Soukup
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lines
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Schmid
authors.affiliation: Academic Endocrine Unit (G.V.W., M.S., B.S.S., K.E.L., R.V.T.), Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; Nuffield Department of Surgical Sciences (G.V.W., B.S.S.), University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Department of Endocrinology (A.B.G.), OCDEM, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; and Novartis Pharma AG (H.A.S.), Novartis Institutes for Biomedical Research, Oncology, CH-4057 Basel, Switzerland.
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051379:Mice; D009377:Multiple Endocrine Neoplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D013004:Somatostatin; C517782:pasireotide