Chordoma Foundation

STAT3

Signal Transducer and Activator of Transcription 3 (STAT3) is a cytoplasmic transcription factor that, when phosphorylated by a Janus Kinase (JAK), becomes activated and regulates the expression of target genes involved in survival, proliferation, self-renewal, and survival.1

Location: Chromosome 17q21

Abnormal activation of STAT3 promotes uncontrolled tumor cell growth and survival by increasing the expression of oncogenes and anti-apoptotic proteins.2

STAT3 in Chordoma

The STAT3 protein is constitutively activated in chordoma tumors. STAT3 is known to be active in other cancers and has been associated with poor prognosis, and studies attempting to clarify its association with chordoma prognosis have reached similar conclusions. Treating chordoma cell lines with STAT3 inhibitors strongly inhibits the growth of the lines, suggesting that drugs that inhibit STAT3 may be of use in treating chordoma patients. This page contains a summary of published research exploring  STAT3 in chordoma and evaluating its inhibition as a potential treatment.

Molecular Evidence


Protein Expression

  • STAT3 is detected in most chordoma tumors and cell lines tested.1 3 SRC, MCL-1, & Bcl-xL, all components of the Stat3 pathway, are also expressed in chordoma samples.1

Protein Activation

  • p-STAT3, the phosphorylated/active form of the STAT3 protein, is detected in virtually all chordoma tumor samples studied by immunohistochemistry and RTK antibody arrays as well as in chordoma cell lines U-CH1, U-CH2, MUC-Chor1, JHC7 and Chor-IN-1.1 2 4 5 6
  • While no correlation has been found between p-STAT3 staining and age, gender, or tumor location, one study found that high p-STAT3 staining was associated with significantly worse prognosis than was low p-STAT3 staining. Recurrent tumors and tumors with metastases also expressed p-STAT3 more intensely than did primary or those without metastases.2 Another study found no correlation with disease-free survival, though correlation with overall survival could not be assessed.4

Preclinical Evidence


In-vitro Efficacy

  • CDDO-Me (+/-doxorubicin or cisplatin): Treatment of 3 chordoma cell lines with this Stat3 inhibitor increased cellular apoptosis, inhibited expression of members of the Stat3 signaling cascade, and inhibited cell line growth. The addition of a chemotherapeutic agent to the treatment regimen was synergisticic, leading to greater cytotoxicity than either agent alone.1
  • SD-1029 (+/-doxorubicin or cisplatin): Treatment of 3 chordoma cell lines with this Stat3 inhibitor increased cellular apoptosis, inhibited expression of members of the Stat3 signaling cascade, and inhibited cell line growth. The addition of a chemotherapeutic agent to the treatment regimen was synergisticic, leading to greater cytotoxicity than either agent alone.2
  • β-β-dimethylacrylshikonin: Treatment of chordoma cell lines with β-β-dimethylacrylshikonin (DMAS) resulted in decreased p-Stat3 protein expression in 2 of 3 cell lines tested.7


References

1.
Yang C, Hornicek F, Wood K, et al. Blockage of Stat3 with CDDO-Me inhibits tumor cell growth in chordoma. Spine (Phila Pa 1976). 2010;35(18):1668-1675. [PubMed]
2.
Yang C, Schwab J, Schoenfeld A, et al. A novel target for treatment of chordoma: signal transducers and activators of transcription 3. Mol Cancer Ther. 2009;8(9):2597-2605. [PubMed]
3.
Tauziéde-Espariat A, Bresson D, Polivka M, et al. Prognostic and Therapeutic Markers in Chordomas: A Study  of 287 Tumors. J Neuropathol Exp Neurol. 2016;75(2):111-120. [PubMed]
4.
Fasig J, Dupont W, LaFleur B, Olson S, Cates J. Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma. Neuropathol Appl Neurobiol. 2008;34(1):95-104. [PubMed]
5.
Dobashi Y, Suzuki S, Sugawara H, Ooi A. Involvement of epidermal growth factor receptor and downstream molecules in bone and soft tissue tumors. Hum Pathol. 2007;38(6):914-925. [PubMed]
6.
Bosotti R, Magnaghi P, Di B, et al. Establishment and genomic characterization of the new chordoma cell line Chor-IN-1. Sci Rep. 2017;7(1):9226. [PubMed]
7.
Zohreh J, Alexander S, Ines A, et al. Influence of Silibinin and  β – β -Dimethylacrylshikonin on Chordoma Cells. P. June 2018. doi:10.1016/j.phymed.2018.06.005