Linked Life Data

17409454

Source:http://linkedlifedata.com/resource/pubmed/id/17409454

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2007-4-5
pubmed:abstractText
Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains approximately 60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser(473) (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr(37/46) (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser(1108) (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr(389) (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3431-40
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:17409454-Animals, pubmed-meshheading:17409454-Antineoplastic Combined Chemotherapy Protocols, pubmed-meshheading:17409454-Child, pubmed-meshheading:17409454-Child, Preschool, pubmed-meshheading:17409454-Disease-Free Survival, pubmed-meshheading:17409454-Female, pubmed-meshheading:17409454-Humans, pubmed-meshheading:17409454-Infant, pubmed-meshheading:17409454-Insulin Receptor Substrate Proteins, pubmed-meshheading:17409454-Male, pubmed-meshheading:17409454-Mice, pubmed-meshheading:17409454-Mice, SCID, pubmed-meshheading:17409454-Phosphoproteins, pubmed-meshheading:17409454-Phosphorylation, pubmed-meshheading:17409454-Protein Kinases, pubmed-meshheading:17409454-Proto-Oncogene Proteins c-akt, pubmed-meshheading:17409454-Rhabdomyosarcoma, pubmed-meshheading:17409454-Signal Transduction, pubmed-meshheading:17409454-Survival Rate, pubmed-meshheading:17409454-TOR Serine-Threonine Kinases, pubmed-meshheading:17409454-Xenograft Model Antitumor Assays
pubmed:year
2007
pubmed:articleTitle
Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival.
pubmed:affiliation
Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Cellular and Gene Therapy, National Cancer Institute, NIH, Bethesda, Maryland, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural