POTENTIAL THERAPEUTIC TARGETS FOR CHONDROSARCOMA

Am J Pathol. 2013 Feb 15. pii: S0002-9440(13)00052-7. doi: 10.1016/j.ajpath.2012.12.036. [Epub ahead of print]
Screening for Potential Targets for Therapy in Mesenchymal, Clear Cell, and Dedifferentiated Chondrosarcoma Reveals Bcl-2 Family Members and TGFβ as Potential Targets.
van Oosterwijk JG, Meijer D, van Ruler MA, van den Akker BE, Oosting J, Krenács T, Picci P, Flanagan AM, Liegl-Atzwanger B, Leithner A, Athanasou N, Daugaard S, Hogendoorn PC, Bovée JV.
Source
Abstract

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.

The mesenchymal, clear cell, and dedifferentiated chondrosarcoma subtypes are extremely rare, together constituting 10% to 15% of all chondrosarcomas. Their poor prognosis and lack of efficacious treatment emphasizes the need to elucidate the pathways playing a pivotal role in these tumors. We constructed tissue microarrays containing 42 dedifferentiated, 23 clear cell, and 23 mesenchymal chondrosarcomas and performed immunohistochemistry to study the expression of growth plate-signaling molecules and molecules shown to be involved in conventional chondrosarcoma. We observed high expression of SOX-9 and FGFR-3, as well as aberrant cellular localization of heparan sulfate proteoglycans, in all subtypes. TGFβ signaling through p-SMAD2 and PAI-1 was highly active in all chondrosarcoma subtypes, which suggests that TGFβ inhibitors as a possible therapeutic strategy in rare chondrosarcoma subtypes. As in conventional chondrosarcoma, antiapoptotic proteins (Bcl-2, and/or Bcl-xl) were highly expressed in all subtypes. Inhibition with the BH-3 mimetic ABT-737 rendered dedifferentiated chondrosarcoma cell lines sensitive to doxorubicin or cisplatin. Our data indicate that antiapoptotic proteins may play an important role in chemoresistance, suggesting a promising role for targeting Bcl-2 family members in chondrosarcoma treatment, irrespective of the subtype.