Identification and validation of therapeutic targets in sarcoma models

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Oncology-Pathology

Sammanfattning: In spite of the low incidence of sarcomas, they are highly aggressive tumors, with high metastatic potential, and resistance to both chemotherapy and radiotherapy, leaving surgery as the only treatment option. There is evidently an urgent need in identifying molecular targets and oncogenic pathways in sarcomas that can be used for the development and evaluation of drugs directed against these tumors. The present projects have been developed to approach this clinical problem. We have evaluated the effect of sorafenib, a receptor tyrosine kinase inhibitor, on soft tissue sarcoma cell lines of various histological subtypes, and we have shown that the growth of rhabdomyosarcoma, in particular, can be suppressed by treatment with sorafenib in vitro and in tumor xenografts, which was mediated through the IGF-1Raxis. These findings open up new possibilities for rhabdomyosarcoma patients, as treatment with sorafenib or anti-IGF-1R agents could be of clinical value. Synovial sarcomas seldom carry p53 mutations. Knowing that HDM2 might have a role in the tumorigenesis of these tumors, we investigated the role of SS18-SSX1 on the function of p53. We found that SS18-SSX1 stabilizes HDM2, thus disrupting the stability and tumor suppressive function of p53 by proteosomal degradation. Inhibition of HDM2 expression could counteract this protective effect of SS18-SSX1 and restore p53. Therefore, targeting the p53-HDM2 autoregulatory loop in could be of benefit in treatment of synovial sarcomas. We made yet another attempt in trying to restore the p53 function in synovial sarcoma. Using tenovin-6, a newly discovered p53 reactivator, we found that p53 levels were restored and we observed an induced cell death upon treatment with tenovin-6 in synovial sarcoma cells. Although this was not directly due to the presence of SS18- SSX1, the expression of SirT2 was inhibited, indicating that agents like tenovin-6 and HDAC inhibitors could be successful in the treatment of synovial sarcoma. Lastly, we have shown that SSX (a cancer-testis antigen) regulates cell cycle progression and is involved in tumor formation through its ability to activatebeta-catenin signalling. Depletion of SSX inhibited tumor growth in vitro and in tumor xenografts. Based on its restricted expression, and together with our findings, we have identified and validated SSX is an ideal molecular target for drug development in anti-cancer treatment.

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