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

N Presneau1, A Shalaby, B Idowu

  • 1UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.

British Journal of Cancer
|April 30, 2009
PubMed

Insights

Chordomas are resistant tumors. This study found that 65% of chordomas may respond to mTOR inhibitors and AKT inhibitors, offering new treatment strategies for this rare cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Chordomas are rare, radio- and chemo-resistant tumors with a high metastatic potential.
  • The PI3K/AKT/TSC1/TSC2/mTOR pathway is implicated in various cancers and presents a potential therapeutic target.
  • Tuberous sclerosis complex syndrome shares molecular links with chordoma, suggesting pathway involvement.

Purpose of the Study:

  • To identify molecular targets for chordoma treatment.
  • To investigate the expression of key molecules within the PI3K/AKT/TSC1/TSC2/mTOR pathway in chordoma tissues.
  • To assess the potential of targeting this pathway for chordoma therapy.

Main Methods:

  • Tissue microarray analysis of 50 chordoma cases using immunohistochemistry.
  • Western blot analysis for selected cases to confirm protein expression.
  • Fluorescence in situ hybridization (FISH) to analyze gene copy numbers for mTOR, RPS6, TSC1, and TSC2.
  • Mutation analysis of PI3KCA and RHEB1 genes.

Main Results:

  • High expression of activated AKT (p-AKT), TSC2 (p-TSC2), and eIF-4E was observed in chordoma tissues.
  • Significant percentages of tumors showed activation of the mTOR pathway (p-mTOR, p-p70S6K).
  • Loss of one copy of mTOR and RPS6 genes was detected in a subset of tumors, correlating with protein loss.

Conclusions:

  • The PI3K/AKT/TSC1/TSC2/mTOR pathway is frequently activated in chordomas.
  • Approximately 65% of studied chordomas may be sensitive to mTOR inhibitors (e.g., rapamycin) and AKT inhibitors.
  • Combined therapeutic strategies targeting both AKT and mTOR pathways show promise for chordoma treatment.

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