) Chemotherapeutic treatment of ovarian cancer remains an integral component in disease management. Many of the protocols used include combinations of platinum based drugs together with paclitaxel. More recent trials suggest that anthracyclines also have significant activity in combination therapy. This component of the SPORE grant is designed to address how resistance to these agents may occur and limit successful therapy. We have secured preliminary data to suggest that platinum and adriamycin resistant cells have enhanced expression of DNA dependent protein kinase (DNA-PK), an enzyme complex with bi-functionality in cell signaling and DNA repair. These properties make the enzyme a particularly attractive subject for study in ovarian cancer models of acquired drug resistance.
Our aims will include: understanding the expression of the catalytic subunit (DNA-PKcs) and the Ku autoantigen (Ku70 and Ku80) in ovarian cancer cell lines acutely and chronically exposed to cis-platinum or adriamycin; extend these in vitro studies into archival and fresh human ovarian biopsy tissues; define the transcriptional and/or post-transcriptional mechanism(s) by which cells increase expression of DNA-PK; compare and contrast the DNA repair properties of the enzyme with the kinase signaling properties; the latter will be determined, in part, by the identification of DNA-PK mediated phosphorylated downstream proteins; characterization of the nature of the DNA-PK inhibitory properties of novel glutathione peptidomimetic drugs; these agents will then be tested as modulators of resistance and preclinical data will be gathered with a view to clinical trial design and implementation. Successful completion of these goals should provide for rational means of improving and extending existing drug treatment approaches for ovarian cancer.
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