Chemoprevention with Somatuline© Delays the Progression of Pancreatic Neuroendocrine Neoplasms in a Mouse Model of Multiple Endocrine Neoplasia Type 1 (MEN1).

ABSTRACT

OBJECTIVE: Long-acting synthetic somatostatin analogues (SSA) are an essential part of the treatment of neuroendocrine neoplasms. We evaluated the chemopreventive effects of a long-acting somatostatin analogue on the development of pancreatic neuroendocrine neoplasms (pNENs) in a genetically engineered MEN1 knockout mouse model. MATERIALS AND METHODS: Heterozygote MEN1 knockout mice were injected every 28 days subcutaneously with the somatostatin analogue lanreotide (Somatuline Autogel©; Ipsen Pharma) or a placebo starting at day 35 after birth. Mice were euthanized after 6, 9, 12, 15 and 18 months, and the size and number of pNENs were measured due histological analysis and compared to the placebo group. RESULTS: The median tumor size of pNENs was statistically significantly smaller after 9 (control group vs. SSA group; 706.476 µm2 vs. 195.271 µm2; p = 0.0012), 12 (placebo group vs. SSA group 822.022 vs. 255.482; p ≤ 0.001), 15 (placebo group vs. SSA group 1192.568 vs. 273.533; p ≤ 0.001) and after 18 months (placebo group vs. SSA group 1328.299 vs. 864.587; p ≤ 0.001) in the SSA group. Comparing the amount of tumors in both groups, a significant reduction was achieved in treated Men1(+/-) mice (41%, p = 0.002). Immunostaining showed, however, no significant difference in the expression of the apoptosis marker caspase-3, but a significant difference in Ki67 index as a marker for tumor cell proliferation (p ≤ 0.005). CONCLUSION: Long-acting somatostatin analogues may be an effective chemopreventive approach to delay the progression of MEN1-associated pNENs. After our preclinical results, we would recommend to evaluate the effects of long-acting SSA in a prospective clinical trial.