STAT3

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
• Preclinical Evidence

Molecular Evidence

Protein Expression

• STAT3 is detected in most chordoma tumors and cell lines tested.^{1 3 4} SRC, MCL-1, & Bcl-xL, all components of the Stat3 pathway, are also expressed in chordoma samples.¹
• Phospho-STAT3 (pSTAT3) was detected in 31/36 pediatric chordoma cases by immunohistochemistry.⁵

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 6 7 8}
• 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.⁶

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.⁹
• FLLL32 (small molecule inhibitor of STAT3): Treatment of chordoma cell lines U-CH1 and UM-Chor1 with 5uM FLLL32 inhibited cell viability and cell proliferation, decreased p-STAT3 protein expression, and increased apoptosis.⁴