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Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models.
J Pharmacol Exp Ther. 2011 Jun; 337(3):644-54.JP

Abstract

Ewing's and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents. Recent data suggest that sarcomas may depend on the insulin-like growth factor type 1 (IGF-1) receptor (IGF1R) and/or the insulin receptor (INSR) to drive tumor growth, survival, and resistance to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We evaluated the therapeutic value of ganitumab (AMG 479; C(6472)H(10028)N(1728)O(2020)S(42)), an anti-IGF1R, fully human monoclonal antibody, alone and in combination with rapamycin (mTORC1 inhibitor) in Ewing's (SK-ES-1 and A673) and osteogenic (SJSA-1) sarcoma models. IGF1R was activated by IGF-1 but not by insulin in each sarcoma model. INSR was also activated by IGF-1 in the SJSA-1 and SK-ES-1 models, but not in the A673 model where insulin was the preferred INSR ligand. Ganitumab significantly inhibited the growth of SJSA-1 and SK-ES-1 xenografts; inhibition was associated with decreased IGF1R and Akt phosphorylation, reduced total IGF1R and bromodeoxyuridine detection, and increased caspase-3 expression. Ganitumab inhibited rapamycin-induced IGF1R, Akt, and glycogen synthase kinase-3β hyperphosphorylation in each sarcoma model. However, ganitumab in combination with rapamycin also resulted in a marked increase in INSR expression and activity in the SJSA-1 and A673 models. The in vivo efficacy of ganitumab in the two ganitumab-sensitive models (SJSA-1 and SK-ES-1) was significantly enhanced in combination with rapamycin. Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that INSR signaling is an important mechanism of resistance to IGF1R blockade.

Authors+Show Affiliations

Oncology Research Therapeutic Area, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. pbeltran@amgen.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21385891

Citation

Beltran, Pedro J., et al. "Efficacy of Ganitumab (AMG 479), Alone and in Combination With Rapamycin, in Ewing's and Osteogenic Sarcoma Models." The Journal of Pharmacology and Experimental Therapeutics, vol. 337, no. 3, 2011, pp. 644-54.
Beltran PJ, Chung YA, Moody G, et al. Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models. J Pharmacol Exp Ther. 2011;337(3):644-54.
Beltran, P. J., Chung, Y. A., Moody, G., Mitchell, P., Cajulis, E., Vonderfecht, S., Kendall, R., Radinsky, R., & Calzone, F. J. (2011). Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models. The Journal of Pharmacology and Experimental Therapeutics, 337(3), 644-54. https://doi.org/10.1124/jpet.110.178400
Beltran PJ, et al. Efficacy of Ganitumab (AMG 479), Alone and in Combination With Rapamycin, in Ewing's and Osteogenic Sarcoma Models. J Pharmacol Exp Ther. 2011;337(3):644-54. PubMed PMID: 21385891.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models. AU - Beltran,Pedro J, AU - Chung,Young-Ah, AU - Moody,Gordon, AU - Mitchell,Petia, AU - Cajulis,Elaina, AU - Vonderfecht,Steven, AU - Kendall,Richard, AU - Radinsky,Robert, AU - Calzone,Frank J, Y1 - 2011/03/08/ PY - 2011/3/10/entrez PY - 2011/3/10/pubmed PY - 2011/7/20/medline SP - 644 EP - 54 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 337 IS - 3 N2 - Ewing's and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents. Recent data suggest that sarcomas may depend on the insulin-like growth factor type 1 (IGF-1) receptor (IGF1R) and/or the insulin receptor (INSR) to drive tumor growth, survival, and resistance to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We evaluated the therapeutic value of ganitumab (AMG 479; C(6472)H(10028)N(1728)O(2020)S(42)), an anti-IGF1R, fully human monoclonal antibody, alone and in combination with rapamycin (mTORC1 inhibitor) in Ewing's (SK-ES-1 and A673) and osteogenic (SJSA-1) sarcoma models. IGF1R was activated by IGF-1 but not by insulin in each sarcoma model. INSR was also activated by IGF-1 in the SJSA-1 and SK-ES-1 models, but not in the A673 model where insulin was the preferred INSR ligand. Ganitumab significantly inhibited the growth of SJSA-1 and SK-ES-1 xenografts; inhibition was associated with decreased IGF1R and Akt phosphorylation, reduced total IGF1R and bromodeoxyuridine detection, and increased caspase-3 expression. Ganitumab inhibited rapamycin-induced IGF1R, Akt, and glycogen synthase kinase-3β hyperphosphorylation in each sarcoma model. However, ganitumab in combination with rapamycin also resulted in a marked increase in INSR expression and activity in the SJSA-1 and A673 models. The in vivo efficacy of ganitumab in the two ganitumab-sensitive models (SJSA-1 and SK-ES-1) was significantly enhanced in combination with rapamycin. Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that INSR signaling is an important mechanism of resistance to IGF1R blockade. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/21385891/Efficacy_of_ganitumab__AMG_479__alone_and_in_combination_with_rapamycin_in_Ewing's_and_osteogenic_sarcoma_models_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21385891 DB - PRIME DP - Unbound Medicine ER -