PMID- 17409454
OWN - NLM
STAT- MEDLINE
DCOM- 20070509
LR  - 20220316
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 7
DP  - 2007 Apr 1
TI  - Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is 
      negatively associated with childhood rhabdomyosarcoma survival.
PG  - 3431-40
AB  - 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.
FAU - Petricoin, Emanuel F 3rd
AU  - Petricoin EF 3rd
AD  - Food and Drug Administration, Center for Biologics Evaluation and Research, 
      Office of Cellular and Gene Therapy, National Cancer Institute, NIH, Bethesda, 
      Maryland, USA.
FAU - Espina, Virginia
AU  - Espina V
FAU - Araujo, Robyn P
AU  - Araujo RP
FAU - Midura, Brieanne
AU  - Midura B
FAU - Yeung, Choh
AU  - Yeung C
FAU - Wan, Xiaolin
AU  - Wan X
FAU - Eichler, Gabriel S
AU  - Eichler GS
FAU - Johann, Donald J Jr
AU  - Johann DJ Jr
FAU - Qualman, Stephen
AU  - Qualman S
FAU - Tsokos, Maria
AU  - Tsokos M
FAU - Krishnan, Kartik
AU  - Krishnan K
FAU - Helman, Lee J
AU  - Helman LJ
FAU - Liotta, Lance A
AU  - Liotta LA
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Disease-Free Survival
MH  - Female
MH  - Humans
MH  - Infant
MH  - Insulin Receptor Substrate Proteins
MH  - Male
MH  - Mice
MH  - Mice, SCID
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rhabdomyosarcoma/drug therapy/*metabolism
MH  - Signal Transduction
MH  - Survival Rate
MH  - TOR Serine-Threonine Kinases
MH  - Xenograft Model Antitumor Assays
EDAT- 2007/04/06 09:00
MHDA- 2007/05/10 09:00
CRDT- 2007/04/06 09:00
PHST- 2007/04/06 09:00 [pubmed]
PHST- 2007/05/10 09:00 [medline]
PHST- 2007/04/06 09:00 [entrez]
AID - 67/7/3431 [pii]
AID - 10.1158/0008-5472.CAN-06-1344 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Apr 1;67(7):3431-40. doi: 10.1158/0008-5472.CAN-06-1344.