title: Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research and Development, Helsinn Therapeutics (US), Inc., Bridgewater, NJ 08807, USA. rnorthrup@helsinnthera.com
authors.forename: R
authors.initials: R
authors.lastname: Northrup
authors.forename: K
authors.initials: K
authors.lastname: Kuroda
authors.forename: E Manning
authors.initials: EM
authors.lastname: Duus
authors.forename: S Routt
authors.initials: SR
authors.lastname: Barnes
authors.forename: L
authors.initials: L
authors.lastname: Cheatham
authors.forename: T
authors.initials: T
authors.lastname: Wiley
authors.forename: C
authors.initials: C
authors.lastname: Pietra
mesh_terms: D000818:Animals; D000855:Anorexia / Q000188:drug therapy; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000139:chemically induced*; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005260:Female; D054439:Ghrelin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000139:chemically induced*; D051379:Mice; D008819:Mice, Nude; D054440:Receptors, Ghrelin / Q000819:agonists*; D015430:Weight Gain / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D054439:Ghrelin; C524461:RC-1291; D054440:Receptors, Ghrelin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone