Influence of tumor-specific epigenetic aberrations on platin resistance of ovarian cancer

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Low survival rates of ovarian cancer patients are caused by missing screening opportunities and a frequent development of platin resistance despite high response rates after first-line treatment. Only clinical parameters are established as prognostic markers and no predictive markers are known. This project will gather data to realize both translational and basic scientific aims. The translational part will validate already identified prognostic and predictive methylation markers for type-II epithelial ovarian cancer and establish new marker combinations. Affected, epigenetically deregulated genes will be functionally analyzed in the second part of the project – aiming to clarify 3 aspects identified in the previous project:(1) Which mechanisms cause the different functions of RUNX3 protein isoforms regarding platin resistance and oncogenic properties? Genome wide ChIP-Seq and gene expression analyses combined with protein-protein interaction mapping will identify isoform-dependent transcriptomes and their regulation.(2) Which DNA repair-systems are affected by TRIB2 – a gene mediating DNA adduct accumulation, G2-M cell cycle arrest, apoptosis and cisplatin sensitivity. Specific environmental stimuli and treatments will activate and modulate DNA repair pathways and enable the identification of TRIB2 effects.(3) Which impacts have Ca2+-associated signaling pathways and their modulation on platin resistance? We have identified several Ca2+-dependent proteins which are hypermethylated in patients with short survival or in platin resistant cells. Measurements of cellular Ca2+-levels in sensitive and resistant cells under cisplatin treatment and the determination of the influence of specific modulations of Ca2+-fluxes will be realized. Moreover, used model systems will be optimized to improve the comparability to the in-vivo situation. Additional to the elucidation of molecular resistance mechanisms the obtained data will enable the identification of strategies to re-sensitize cells to platin potentially modulating the long-term response to platin chemotherapy in the future.