PROJECT SUMMARY/ABSTRACT A major problem in ovarian serous carcinoma is that cancers often develop a high degree of resistance to taxane-platinum combination treatment. For cancer cells, induction of drug efflux transporters has been shown to act as a protective mechanism to mediate the resistance to both, paclitaxel and platinum drugs. Thus, the inhibition of expression of these proteins may re-sensitize previously resistant cancer cells and augment cytotoxicity of such combination therapy. Our preliminary data indicate gene amplification and overexpression of ERK7 in approximately 34-36% of human ovarian cancers. Based on our preliminary data, it is our hypothesis that amplification of ERK7 in ovarian serous carcinoma contributes to resistance to taxane- platinum treatment; and that chemical inhibition of ERK7 can re-sensitize cancer cells to such combination therapy. To test this we will: Determine the functional relation between ERK7 and expression of multidrug resistance genes in ovarian cancer cells and patient samples (Specific Aim 1); Determine if inhibition of ERK7 re-sensitizes drug resistant ovarian cancer cell lines to taxane-platinum treatment (Specific Aim 2); Test the efficacy of a novel ERK7 inhibitor in vivo using relevant animal models (Specific Aim 3). Successful completion of our project will i) identify upregulation of ERK7 as a molecular marker for taxane- platinum resistant ovarian cancer; ii) identify ERK7 as a novel target in ovarian cancer; and iii) test in vivo if targeting ERK7 is a valuable strategy to re-sensitize cancers to taxane-platinum therapy. Our work will provide mechanistic insight into how taxane-platinum resistance occurs, but also provide the groundwork for development of inhibitors targeting ERK7.
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