Supportive Care in Cancer

, Volume 21, Issue 9, pp 2409–2415 | Cite as

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

  • R. NorthrupEmail author
  • K. Kuroda
  • E. Manning Duus
  • S. Routt Barnes
  • L. Cheatham
  • T. Wiley
  • C. Pietra
Original Article



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.


Anamorelin 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.


  1. 1.
    Tisdale MJ (2002) Cachexia in cancer patients. Nat Rev Cancer 2:862–871CrossRefGoogle Scholar
  2. 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. 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. 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
  5. 5.
    Reid J, McKenna H, Fitzsimons D, McCance T (2009) The experience of cancer cachexia: a qualitative study of advanced cancer patients and their family members. Int J Nurs Stud 46:606–616CrossRefGoogle Scholar
  6. 6.
    McClement S (2005) Cancer anorexia-cachexia syndrome: psychological effect on the patient and family. J Wound Ostomy Continence Nurs 32:264–268CrossRefGoogle Scholar
  7. 7.
    Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M, Kangawa K (2005) International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev 57:541–546CrossRefGoogle Scholar
  8. 8.
    Akamizu T, Kangawa K (2010) Ghrelin for cachexia. J Cachex Sarcopenia Muscle 1:169–176CrossRefGoogle Scholar
  9. 9.
    Khan AS, Smith LC, Anscombe IW, Cummings KK, Pope MA, Draghia-Akli R (2005) Growth hormone releasing hormone plasmid supplementation, a potential treatment for cancer cachexia, does not increase tumor growth in nude mice. Cancer Gene Ther 12:54–60CrossRefGoogle Scholar
  10. 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
  11. 11.
    Kim HJ, Kim HJ, Yun J, Kim KH, Kim SH, Lee SC, Bae SB, Kim CK, Lee NS, Lee KT, Park SK, Won JH, Park HS, Hong DS (2012) Pathophysiological role of hormones and cytokines in cancer cachexia. J Korean Med Sci 27:128–134CrossRefGoogle Scholar
  12. 12.
    Garcia JM, Polvino WJ (2007) Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers. Oncologist 12:594–600CrossRefGoogle Scholar
  13. 13.
    Garcia JM, Polvino WJ (2009) Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Horm IGF Res 19:267–273CrossRefGoogle Scholar
  14. 14.
    Garcia JM, Friend J, Allen S (2012) Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study. Support Care Cancer 21:129–137CrossRefGoogle Scholar
  15. 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
  16. 16.
    Jenkins PJ, Bustin SA (2004) Evidence for a link between IGF-I and cancer. Eur J Endocrinol 151(Suppl 1):S17–S22CrossRefGoogle Scholar
  17. 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
  18. 18.
    Nikolopoulos D, Theocharis S, Kouraklis G (2010) Ghrelin: a potential therapeutic target for cancer. Regul Pept 163:7–17CrossRefGoogle Scholar
  19. 19.
    Chopin L, Walpole C, Seim I, Cunningham P, Murray R, Whiteside E, Josh P, Herington A (2011) Ghrelin and cancer. Mol Cell Endocrinol 340:65–69CrossRefGoogle Scholar
  20. 20.
    Baxter RC (2001) Signalling pathways involved in antiproliferative effects of IGFBP-3: a review. Mol Pathol 54:145–148CrossRefGoogle Scholar
  21. 21.
    National Research Council (1996) Guide for the care and use of laboratory Animals. National Research Council, Washington, D.CGoogle Scholar
  22. 22.
    Hickey GJ, Jacks TM, Schleim KD, Frazier E, Chen HY, Krupa D, Feeney W, Nargund RP, Patchett AA, Smith RG (1997) Repeat administration of the GH secretagogue MK-0677 increases and maintains elevated IGF-I levels in beagles. J Endocrinol 152:183–192CrossRefGoogle Scholar
  23. 23.
    Khan AS, Anscombe IW, Cummings KK, Pope MA, Smith LC, Draghia-Akli R (2003) Effects of plasmid-mediated growth hormone-releasing hormone supplementation on LL-2 adenocarcinoma in mice. Mol Ther 8:459–466CrossRefGoogle Scholar
  24. 24.
    Koo GC, Huang C, Camacho R, Trainor C, Blake JT, Sirotina-Meisher A, Schleim KD, Wu TJ, Cheng K, Nargund R, McKissick G (2001) Immune enhancing effect of a growth hormone secretagogue. J Immunol 166:4195–4201CrossRefGoogle Scholar
  25. 25.
    Perboni S, Bowers C, Kojima S, Asakawa A, Inui A (2008) Growth hormone releasing peptide 2 reverses anorexia associated with chemotherapy with 5-fluorouracil in colon cancer cell-bearing mice. World J Gastroenterol 14:6303–6305CrossRefGoogle Scholar
  26. 26.
    DeBoer MD, Zhu XX, Levasseur P, Meguid MM, Suzuki S, Inui A, Taylor JE, Halem HA, Dong JZ, Datta R, Culler MD, Marks DL (2007) Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia. Endocrinology 148:3004–3012CrossRefGoogle Scholar
  27. 27.
    Farris GM, Miller GK, Wollenberg GK, Molon-Noblot S, Chan C, Prahalada S (2007) Recombinant rat and mouse growth hormones: risk assessment of carcinogenic potential in 2-year bioassays in rats and mice. Toxicol Sci 97:548–561CrossRefGoogle Scholar
  28. 28.
    Costelli P, Muscaritoli M, Bossola M, Penna F, Reffo P, Bonetto A, Busquets S, Bonelli G, Lopez-Soriano FJ, Doglietto GB, Argilés JM, Baccino FM, Rossi Fanelli F (2006) IGF-1 is downregulated in experimental cancer cachexia. Am J Physiol Regul Integr Comp Physiol 291:R674–R683CrossRefGoogle Scholar
  29. 29.
    Schmidt K, von Haehling S, Doehner W, Palus S, Anker SD, Springer J (2011) IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexia. J Cachex Sarcopenia Muscle 2:105–109CrossRefGoogle Scholar

Copyright information

© The Author(s) 2013

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • R. Northrup
    • 1
    • 5
    Email author
  • K. Kuroda
    • 2
  • E. Manning Duus
    • 1
  • S. Routt Barnes
    • 3
  • L. Cheatham
    • 3
  • T. Wiley
    • 3
  • C. Pietra
    • 4
  1. 1.Research and DevelopmentHelsinn Therapeutics (U.S.), Inc.BridgewaterUSA
  2. 2.Safety Research LaboratoriesOno PharmaceuticalFukuiJapan
  3. 3.Charles River Discovery Research ServicesMorrisvilleUSA
  4. 4.Research and Preclinical DevelopmentHelsinn HealthcareLuganoSwitzerland
  5. 5.Safety AssessmentHelsinn Therapeutics (U.S.), Inc.BridgewaterUSA

Personalised recommendations