Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway

[No Value] Presneau, A. Shalaby, B. Idowu, P. Gikas, S. R. Cannon, I. Gout, T. Diss, R. Tirabosco, A. M. Flanagan

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Abstract

Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of chordoma. In view of the reported association of chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.

Original languageEnglish
Pages (from-to)1406-1414
Number of pages9
JournalBritish Journal of Cancer
Volume100
Issue number9
DOIs
Publication statusPublished - May 5 2009

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Chordoma
Phosphatidylinositol 3-Kinases
70-kDa Ribosomal Protein S6 Kinases
Fluorescence In Situ Hybridization
Therapeutics
Chromosomes, Human, Pair 10
Tuberous Sclerosis
Sirolimus
Radio
Phosphoric Monoester Hydrolases
Genes
Neoplasms
Western Blotting
Immunohistochemistry
Drug Therapy
Mutation
DNA
Proteins

Keywords

  • AKT
  • Brachyury
  • Chordoma
  • MTOR
  • Rapamycin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Presneau, N. V., Shalaby, A., Idowu, B., Gikas, P., Cannon, S. R., Gout, I., ... Flanagan, A. M. (2009). Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. British Journal of Cancer, 100(9), 1406-1414. https://doi.org/10.1038/sj.bjc.6605019

Potential therapeutic targets for chordoma : PI3K/AKT/TSC1/TSC2/mTOR pathway. / Presneau, [No Value]; Shalaby, A.; Idowu, B.; Gikas, P.; Cannon, S. R.; Gout, I.; Diss, T.; Tirabosco, R.; Flanagan, A. M.

In: British Journal of Cancer, Vol. 100, No. 9, 05.05.2009, p. 1406-1414.

Research output: Contribution to journalArticle

Presneau, NV, Shalaby, A, Idowu, B, Gikas, P, Cannon, SR, Gout, I, Diss, T, Tirabosco, R & Flanagan, AM 2009, 'Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway', British Journal of Cancer, vol. 100, no. 9, pp. 1406-1414. https://doi.org/10.1038/sj.bjc.6605019
Presneau, [No Value] ; Shalaby, A. ; Idowu, B. ; Gikas, P. ; Cannon, S. R. ; Gout, I. ; Diss, T. ; Tirabosco, R. ; Flanagan, A. M. / Potential therapeutic targets for chordoma : PI3K/AKT/TSC1/TSC2/mTOR pathway. In: British Journal of Cancer. 2009 ; Vol. 100, No. 9. pp. 1406-1414.
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abstract = "Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40{\%} of patients. The aim of this study was to identify potential molecular targets for the treatment of chordoma. In view of the reported association of chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92{\%}), p-TSC2 (96{\%}), p-mTOR (27{\%}), total mTOR (75{\%}), p-p70S6K (62{\%}), p-RPS6 (22{\%}), p-4E-BP1 (96{\%}) and eIF-4E (98{\%}). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16{\%} of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65{\%} of the chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.",
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