Towards new therapeutic strategies in chondrosarcoma

Schrage, Y.M.

This thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which identified Src inhibitor dasatinib as a potential target in chondrosarcoma treatment. Subsequently, growth of the majority of chondrosarcoma cell cultures was inhibited by dasatinib. In addition to dasatinib, CDK inhibitor Flavoperidol, Aurorakinase inhibitor AZD1152 and AKT inhibitor Enzastaurin were identified as candidates for therapeutic intervention in chondrosarcomas. Moreover, the use of selective COX-2 inhibition was evaluated preclinically. In vitro, chondrosarcoma cell viability was inhibited by celecoxib, a selective COX-2 inhibitor. Also in a grade II and III chondrosarcoma xenograft mouse model an anti- tumourigenic effect of celecoxib was found, since tumor size was negatively...Show moreThis thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which identified Src inhibitor dasatinib as a potential target in chondrosarcoma treatment. Subsequently, growth of the majority of chondrosarcoma cell cultures was inhibited by dasatinib. In addition to dasatinib, CDK inhibitor Flavoperidol, Aurorakinase inhibitor AZD1152 and AKT inhibitor Enzastaurin were identified as candidates for therapeutic intervention in chondrosarcomas. Moreover, the use of selective COX-2 inhibition was evaluated preclinically. In vitro, chondrosarcoma cell viability was inhibited by celecoxib, a selective COX-2 inhibitor. Also in a grade II and III chondrosarcoma xenograft mouse model an anti- tumourigenic effect of celecoxib was found, since tumor size was negatively correlated to celecoxib serum levels. The results described in this thesis have led to a better understanding of molecular events that are important in the growth of conventional chondrosarcoma. In addition, new targets were identified, which are expected to lead to the implementation of new therapy modalities for patients that have inoperable or metastatic chondrosarcoma.Show less

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Towards new therapeutic strategies in chondrosarcoma

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