Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model
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Anamorelin (ONO-7643) is an orally active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia. It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH). However, increasing GH and insulin-like growth factor-1 in cancer patients raises concerns of potentially stimulating tumor growth. Therefore, we investigated the effect of ghrelin and anamorelin on tumor growth in a murine NSCLC xenograft model.
Female nude mice (15–21/group) with established A549 tumors were administered ghrelin (2 mg/kg i.p.), anamorelin (3, 10, or 30 mg/kg p.o.), or vehicle controls daily for 28 days. Tumor growth, food consumption, and body weight were monitored. Murine growth hormone (mGH) and murine insulin-like growth factor-1 (mIGF-1) were measured in plasma.
Tumor growth progressed throughout the study, with no significant differences between treatment groups. Daily food consumption was also relatively unchanged, while the percentage of mean body weight gain at the end of treatment was significantly increased in animals administered 10 and 30 mg/kg compared with controls (p < 0.01). Peak mGH levels were significantly higher in ghrelin- and anamorelin-treated animals than in controls, while peak mIGF-1 levels were slightly elevated but not statistically significant. All regimens were well tolerated.
These findings demonstrate that neither anamorelin nor ghrelin promoted tumor growth in this model, despite increased levels of mGH and a trend of increased mIGF-1. Together with anamorelin’s ability to increase body weight, these results support the clinical development of ghrelin receptor agonist treatments for managing NSCLC-related anorexia/cachexia.
KeywordsAnamorelin Cachexia Ghrelin Growth hormone IGF-1 Non-small cell lung cancer
This study was co-sponsored by Helsinn and Ono Pharmaceutical Co., Ltd, and conducted at Charles River Discovery Research Services, Morrisville, NC, USA (Piedmont Research Center). The authors would like to acknowledge Alan Meshaw for his contribution to statistical analysis. Editorial assistance was provided by Elena Palmesino (Helsinn Healthcare, Lugano, Switzerland) and Sandra Mendes (TRM Oncology, The Hague, The Netherlands), funded by Helsinn.
Conflicts of interest
Robert Northrup and Elizabeth Manning Duus are employees of Helsinn Therapeutics (U.S.), Inc, and Claudio Pietra is an employee of Helsinn Healthcare. Ken Kuroda was an employee of Ono Pharmaceuticals. Sheri Routt Barnes, Lynn Cheatham, and Tim Wiley are employees of Charles River Discovery Research Services, a company which was paid by Helsinn and Ono to conduct this study. The authors have full control of the primary data and agree to allow the journal to review their data if requested.
- 2.Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, Macdonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489–495CrossRefGoogle Scholar
- 3.Arrieta O, Michel Ortega RM, Villanueva-Rodríguez G, Serna-Thomé MG, Flores-Estrada D, Diaz-Romero C, Rodríguez CM, Martínez L, Sánchez-Lara K (2010) Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxel–cisplatin chemotherapy: a prospective study. BMC Cancer 10:50CrossRefGoogle Scholar
- 4.Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO Jr, Engstrom PF, Ezdinli EZ, Horton J, Johnson GJ, Moertel CG, Oken MM, Perlia C, Rosenbaum C, Silverstein MN, Skeel RT, Sponzo RW, Tormey DC (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 69:491–497CrossRefGoogle Scholar
- 10.Strasser F, Lutz TA, Maeder MT, Thuerlimann B, Bueche D, Tschöp M, Kaufmann K, Holst B, Brändle M, von Moos R, Demmer R, Cerny T (2008) Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, doubleblind, double-crossover study. Br J Cancer 98:300–308CrossRefGoogle Scholar
- 15.Garcia J, Boccia RV, Graham C, Kumor K, Polvino W (2007) A phase II randomized, placebo controlled, double-blind study of the efficacy and safety of RC-1291 (RC) for the treatment of cancer cachexia [abstract]. American Society of Clinical Oncology (ASCO) annual meeting. J Clin Oncol 25:9133CrossRefGoogle Scholar
- 17.Shariat SF, Lamb DJ, Kattan MW, Nguyen C, Kim J, Beck J, Wheeler TM, Slawin KM (2002) Association of preoperative plasma levels of insulin-like growth factor I and insulin-like growth factor binding proteins-2 and −3 with prostate cancer invasion, progression, and metastasis. J Clin Oncol 20:833–841CrossRefGoogle Scholar
- 21.National Research Council (1996) Guide for the care and use of laboratory Animals. National Research Council, Washington, D.CGoogle Scholar
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