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Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.

Publication ,  Journal Article
Sommer, J; Itani, DM; Homlar, KC; Keedy, VL; Halpern, JL; Holt, GE; Schwartz, HS; Coffin, CM; Kelley, MJ; Cates, JMM
Published in: J Pathol
April 2010

Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.

Duke Scholars

Published In

J Pathol

DOI

EISSN

1096-9896

Publication Date

April 2010

Volume

220

Issue

5

Start / End Page

608 / 617

Location

England

Related Subject Headings

  • Young Adult
  • Tissue Array Analysis
  • Survival Analysis
  • Signal Transduction
  • Receptor, IGF Type 1
  • Purine-Nucleoside Phosphorylase
  • Prognosis
  • Phosphorylation
  • Pathology
  • Notochord
 

Citation

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Sommer, J., Itani, D. M., Homlar, K. C., Keedy, V. L., Halpern, J. L., Holt, G. E., … Cates, J. M. M. (2010). Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol, 220(5), 608–617. https://doi.org/10.1002/path.2679
Sommer, Josh, Doha M. Itani, Kelly C. Homlar, Vicki L. Keedy, Jennifer L. Halpern, Ginger E. Holt, Herbert S. Schwartz, Cheryl M. Coffin, Michael J. Kelley, and Justin M. M. Cates. “Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.J Pathol 220, no. 5 (April 2010): 608–17. https://doi.org/10.1002/path.2679.
Sommer J, Itani DM, Homlar KC, Keedy VL, Halpern JL, Holt GE, et al. Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol. 2010 Apr;220(5):608–17.
Sommer, Josh, et al. “Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.J Pathol, vol. 220, no. 5, Apr. 2010, pp. 608–17. Pubmed, doi:10.1002/path.2679.
Sommer J, Itani DM, Homlar KC, Keedy VL, Halpern JL, Holt GE, Schwartz HS, Coffin CM, Kelley MJ, Cates JMM. Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol. 2010 Apr;220(5):608–617.
Journal cover image

Published In

J Pathol

DOI

EISSN

1096-9896

Publication Date

April 2010

Volume

220

Issue

5

Start / End Page

608 / 617

Location

England

Related Subject Headings

  • Young Adult
  • Tissue Array Analysis
  • Survival Analysis
  • Signal Transduction
  • Receptor, IGF Type 1
  • Purine-Nucleoside Phosphorylase
  • Prognosis
  • Phosphorylation
  • Pathology
  • Notochord