|
rdf:type |
|
|
lifeskim:mentions |
umls-concept:C0003241,
umls-concept:C0035412,
umls-concept:C0085281,
umls-concept:C0140080,
umls-concept:C0164786,
umls-concept:C0205250,
umls-concept:C0205265,
umls-concept:C0599894,
umls-concept:C0812228,
umls-concept:C1334088,
umls-concept:C1555582,
umls-concept:C1704259,
umls-concept:C1705987,
umls-concept:C1709059
|
|
pubmed:issue |
19
|
|
pubmed:dateCreated |
2008-10-2
|
|
pubmed:abstractText |
Insulin-like growth factor I receptor (IGF-IR) and its ligands are overexpressed by tumors, mediating proliferation and protecting against stress-induced apoptosis. Accordingly, there has been a considerable amount of interest in developing therapeutic agents against IGF-IR. IGF-IR is believed to be ubiquitously expressed without detectable mutation or amplification in cancer. We explored the determinants of cellular response to a humanized anti-IGF-IR antibody. Our results showed a large variation in IGF-IR levels in rhabdomyosarcoma tumor specimens that were comparable with those in rhabdomyosarcoma cell lines. In vitro analysis revealed a direct and very significant correlation between elevated IGF-IR levels and antiproliferative effects of the antibody and defined a receptor number that would predict sensitivity. Our data further suggested a strong dependence on IGF-IR for AKT signaling in cells with elevated IGF-IR. The sensitivity of the high IGF-IR-expressing cells was blocked with a constitutively active AKT. The extracellular signal-regulated kinase pathway was not affected by the antibody. In vivo studies showed that anti-IGF-IR had single-agent antitumor activity; furthermore, predictions of responses based on IGF-IR levels were accurate. In vivo biomarker analysis suggested that h7C10 down-regulated both IGF-IR and p-AKT initially, concordant with antitumor activity. Subsequent progression of tumors was associated with reactivation of p-AKT despite sustained suppression of IGF-IR. These results identified the first predictive biomarker for anti-IGF-IR therapies in cancer.
|
|
pubmed:grant |
|
|
pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-12067807,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-12483226,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-12566306,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-12767520,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-14603261,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-14695208,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15050909,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15050914,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15050915,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15110491,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15193254,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15386423,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15756033,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15837762,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15867386,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-15928295,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16001956,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16083341,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16093437,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16287993,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16341064,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16621671,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16844299,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-16947084,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-17001314,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-17346182,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-17604717,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-17692802,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-17898809,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-17906644,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-2177632,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-2553250,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-2553774,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-3262110,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-7923191,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-8083365,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-8402901,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18829562-8402902
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Oct
|
|
pubmed:issn |
1538-7445
|
|
pubmed:author |
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
1
|
|
pubmed:volume |
68
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
8039-48
|
|
pubmed:dateRevised |
2011-9-26
|
|
pubmed:meshHeading |
pubmed-meshheading:18829562-Humans,
pubmed-meshheading:18829562-Animals,
pubmed-meshheading:18829562-Mice,
pubmed-meshheading:18829562-Antibodies,
pubmed-meshheading:18829562-Neoplasms, Hormone-Dependent,
pubmed-meshheading:18829562-Female,
pubmed-meshheading:18829562-Rhabdomyosarcoma,
pubmed-meshheading:18829562-Tumor Cells, Cultured,
pubmed-meshheading:18829562-Immunotherapy,
pubmed-meshheading:18829562-Cell Proliferation,
pubmed-meshheading:18829562-Signal Transduction,
pubmed-meshheading:18829562-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:18829562-Drug Resistance, Neoplasm,
pubmed-meshheading:18829562-Insulin-Like Growth Factor I,
pubmed-meshheading:18829562-Drug Delivery Systems,
pubmed-meshheading:18829562-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:18829562-Receptor, IGF Type 1
|
