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

Presneau, N; Shalaby, A; Idowu, B; Gikas, P; Cannon, SR; Gout, I; Diss, T; ... Flanagan, AM; + view all (2009) Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. Br.J.Cancer , 100 (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

Type: Article
Title: Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway
Additional information: DA - 20090429 IS - 1532-1827 (Electronic) IS - 0007-0920 (Linking) LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't RN - 0 (CRTC2 protein, human) RN - 0 (Transcription Factors) RN - 0 (Tumor Suppressor Proteins) RN - 0 (mTORC1 protein, human) RN - 0 (tuberous sclerosis complex 1 protein) RN - 169027-60-5 (tuberous sclerosis complex 2 protein) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM
Keywords: 1-Phosphatidylinositol 3-Kinase, genetics, metabolism, Adult, Aged, Aged,80 and over, Blotting,Western, Chordoma, pathology, Female, Humans, Immunohistochemistry, In Situ Hybridization,Fluorescence, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Protein Array Analysis, Proto-Oncogene Proteins c-akt, antagonists & inhibitors, Transcription Factors, Tuberous Sclerosis, drug therapy, Tumor Suppressor Proteins, Young Adult
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/104279
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