Effect of anamorelin/ONO-7643, a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.

Abstract

e19577 Background: Anamorelin/ONO-7643 is an orally-active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related cachexia/anorexia. It displays both anabolic and orexigenic properties via its ghrelin and growth hormone (GH) secretagogue activity. However, increasing GH and insulin-like growth factor-1 (IGF-1) in cancer patients raises potential concerns of stimulating tumor growth. In this study, we investigated the effect of ghrelin and Anamorelin/ONO-7643 on tumor growth in a NSCLC xenograft model. Methods: On Day 1 (D1), 21 days after implanting A549 tumors, female nude mice were sorted into six groups (n=15/group) and administered ghrelin (2 mg/kg i.p.), Anamorelin/ONO-7643 (3, 10, or 30 mg/kg p.o.) or vehicles (saline i.p. or de-ionized water p.o.) for 28 days, starting on D3. Tumor growth, body weight, and food consumption were monitored. Mice used to assess plasma levels of murine GH (mGH) and IGF-1 (mIGF-1) were sorted into three groups (n=21/group) and treated for 28 days with ghrelin, the high dose of Anamorelin/ONO-7643 or vehicle (de-ionized water p.o.). Results: After 28 days of treatment, there was no difference in median tumor volumes (D30 values: 1008, 936, 1080, 666 and 847 mm3 for vehicle, ghrelin and Anamorelin/ONO-7643 at 3, 10 and 30 mg/kg, respectively). Ghrelin significantly increased mGH compared to controls, while Anamorelin/ONO-7643 modestly increased mGH. Peak mIGF-1 levels were slightly higher in animals given ghrelin or Anamorelin/ONO-7643 compared to vehicle, although not significantly. Anamorelin/ONO-7643 at 10 and 30 mg/kg/day showed a statistically significant (p<0.01) increase in body weight from D1 to D30 compared to control animals, with no change in food consumption. Ghrelin treatment had no effect on body weight or food consumption. Conclusions: Anamorelin/ONO-7643 or ghrelin treatment for 28 days had no effect on tumor growth in A549 tumor-bearing nude mice, despite increased mGH and a trend of increased mIGF-1. Anamorelin/ONO-7643 also significantly increased body weight at 10 and 30 mg/kg/day. These results support using ghrelin receptor agonist-based treatments in managing NSCLC-related cachexia/anorexia.