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; C6472H10028N1728O2020S42), 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.
Footnotes
This study was funded by Amgen Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.178400.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- IGF
- insulin-like growth factor
- IGF1R
- IGF type 1 receptor
- pIGF1R
- phosphorylated IGF1R
- tIGF1R
- total IGF1R
- pAkt
- phosphorylated Akt
- tAkt
- total Akt
- mTOR
- mammalian target of rapamycin
- mTORC1
- mTOR complex 1
- IRS-1
- insulin receptor substrate 1
- pIRS-1
- phosphorylated IRS-1
- tIRS-1
- total IRS-1
- INSR
- insulin receptor
- pINSR
- phosphorylated INSR
- tINSR
- total INSR
- pp70S6K
- phosphorylated p70S6K
- tp70S6K
- total p70S6K
- GSK3β
- glycogen synthase kinase-3β
- pGSK3β
- phosphorylated GSK3β
- tGSK3β
- total GSK3β
- p:t
- phosphorylated/total
- PI3K
- phosphatidylinositol-3-kinase
- MSD
- Meso Scale Discovery
- BrdU
- bromodeoxyuridine
- FBS
- fetal bovine serum
- DMEM
- Dulbecco's modified Eagle medium
- PBS
- phosphate-buffered saline
- IC50
- half-maximal inhibitory concentration
- TBS
- Tris-buffered saline
- RLU
- relative light units
- hIgG1
- human IgG1
- AMG 479
- C6472H10028N1728O2020S42
- ANOVA
- analysis of variance.
- Received December 21, 2010.
- Accepted February 23, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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