1R21CA222425-01A1 (R21) ApplID: 9581676 | |||
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Title | Targeting chemoresistance in ovarian cancer | ||
Institution | MAYO CLINIC JACKSONVILLE, JACKSONVILLE, FL | ||
Principal Investigator | STORZ, PETER | NCI Program Director | Chen |
Cancer Activity | Biochemistry and Pharmacology | Division | DCTD |
Funded Amount | $219,491 | Project Dates | 08/01/2018 - 07/31/2020 |
Fiscal Year | 2018 | Project Type | Grant |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (100.0%) Taxol (100.0%) |
Ovarian Cancer (100.0%) | ||
Research Type | |||
Systemic Therapies - Discovery and Development | |||
Abstract | |||
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." |