Emerging therapeutic targets for synovial sarcoma

Abstract

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.

Keywords::

• CXCR4
• HDAC inhibitors
• IGFR-1R
• mTOR
• notch
• NY-ESO-1
• soft tissue sarcoma
• synovial sarcoma
• therapeutic targets
• VEGFR

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Pazopanib, a multikinase inhibitor targeting VEGF, PDGF, showed activity in synovial sarcoma (SS), and it is presently commercially available.

• A synergistic activity with ifosfamide has been showed for sorafenib.

• New molecular investigations are needed in order to identify patients with SS who are more likely to have clinical benefit from tyrosine kinase inhibitors in monotherapy.

• Chemotaxis markers such as chemotaxis receptor 4 have prognostic significance in SS and could represent a new therapeutic target.

• Cixutumumab, an anti-IGF1R antibody, in combination with temsirolimus, a mTOR inhibitor, showed no activity in SS.

• Specific dendritic cell immunotherapy in combination with chemotherapy is an interesting and potentially active therapy for SS.

• The notch and Hedgehog signaling pathways are promising targets in SS.

• Targeting epigenetic misregulation in SS is worth studying.

Notes