This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petricoin, E. F. Articles by Liotta, L. A. Search for Related Content PubMed PubMed Citation Articles by Petricoin, E. F., III Articles by Liotta, L. A.

Phosphoprotein Pathway Mapping: Akt/Mammalian Target of Rapamycin Activation Is Negatively Associated with Childhood Rhabdomyosarcoma Survival

¹ Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Cellular and Gene Therapy; ² Laboratory of Pathology, ³ Department of Pediatric Oncology, and ⁴ Genomics and Bioinformatics Group, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; and ⁵ Department of Pathology, Columbus Children's Hospital, Columbus, Ohio

Requests for reprints: Virginia Espina, George Mason University, Center for Applied Proteomics and Molecular Medicine, 10900 University Boulevard MS 1A9, Manassas, VA 20110. Phone: 703-993-8062; Fax: 703-993-8606; E-mail: vespina{at}gmu.edu.

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 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 Ser⁴⁷³ (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 Ser¹¹⁰⁸ (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr³⁸⁹ (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. [Cancer Res 2007;67(7):3431–40]

This article has been cited by other articles:

				Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas Mol. Cancer Ther., November 1, 2009; 8(11): 3024 - 3035.

				J. D. Murphy, A. C. Spalding, Y. R. Somnay, S. Markwart, M. E. Ray, and D. A. Hamstra Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature Clin. Cancer Res., January 15, 2009; 15(2): 589 - 596. [Abstract] [Full Text] [PDF]

				V. Espina, K. H. Edmiston, M. Heiby, M. Pierobon, M. Sciro, B. Merritt, S. Banks, J. Deng, A. J. VanMeter, D. H. Geho, et al. A Portrait of Tissue Phosphoprotein Stability in the Clinical Tissue Procurement Process Mol. Cell. Proteomics, October 1, 2008; 7(10): 1998 - 2018. [Abstract] [Full Text] [PDF]

				A. J. VanMeter, A. S. Rodriguez, E. D. Bowman, J. Jen, C. C. Harris, J. Deng, V. S. Calvert, A. Silvestri, C. Fredolini, V. Chandhoke, et al. Laser Capture Microdissection and Protein Microarray Analysis of Human Non-small Cell Lung Cancer: Differential Epidermal Growth Factor Receptor (EGPR) Phosphorylation Events Associated with Mutated EGFR Compared with Wild Type Mol. Cell. Proteomics, October 1, 2008; 7(10): 1902 - 1924. [Abstract] [Full Text] [PDF]

				O. Oberlin, A. Rey, E. Lyden, G. Bisogno, M. C.G. Stevens, W. H. Meyer, M. Carli, and J. R. Anderson Prognostic Factors in Metastatic Rhabdomyosarcomas: Results of a Pooled Analysis From United States and European Cooperative Groups J. Clin. Oncol., May 10, 2008; 26(14): 2384 - 2389. [Abstract] [Full Text] [PDF]

				N. Rhodes, D. A. Heerding, D. R. Duckett, D. J. Eberwein, V. B. Knick, T. J. Lansing, R. T. McConnell, T. M. Gilmer, S.-Y. Zhang, K. Robell, et al. Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity Cancer Res., April 1, 2008; 68(7): 2366 - 2374. [Abstract] [Full Text] [PDF]

				R. T. Kurmasheva, J. B. Easton, and P. J. Houghton Combined Targeting of mTOR and the Insulin-like Growth Factor Pathway ASCO Educational Book, January 1, 2008; 2008(1): 460 - 464. [Abstract] [Full Text] [PDF]

				X. Wan and L. J. Helman The Biology Behind mTOR Inhibition in Sarcoma Oncologist, August 1, 2007; 12(8): 1007 - 1018. [Abstract] [Full Text] [PDF]