A screening based approach to find new paths for targeted treatment in chondrosarcoma

Chondrosarcomas are malignant cartilage producing tumours, occurring mostly around the age of fifty. Treatment is mainly by surgery, since tumours are relatively resistant toward chemo-and radiotherapy. This means that patients with inoperable disease have no alternative treatment options. In this thesis we describe the use of compound and siRNA screens to identify new targeted treatment options for patients with chondrosarcoma. Using available chondrosarcoma cell lines as a model we investigated apoptotic proteins, kinases and metabolic regulators in a non-biased way to identify most promising hits. In addition the role of individual Bcl-2 family members Bcl-2, Bcl-xl and Bcl-w was investigated. Results reveal a role for Bcl-2 family member Bcl-xl, anti-apoptotic and cell cycle regulator Survivin, cell cycle regulators AURKA, CHK1 and PLK1 and mTOR as important survival proteins in chondrosarcoma. Moreover treatment with Bcl-xl or CHK1 inhibitors could chemo-sensitize a subset of chondrosarcoma cell lines. Furthermore alterations in the Rb1 pathway have been identified as a marker for radio resistance in chondrosarcoma patient samples. Collectively these studies identify several lead targets that might be useful as targeted treatment options for chondrosarcoma patients. Future research should focus more on the therapeutic value of these targets, and translate these pre-clinical findings to clinical practise.