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.

Public Health Relevance

A major problem in treatment of ovarian carcinoma is that cancers often develop a high degree of resistance to taxane-platinum therapy. This proposal will investigate the role of ERK7 in mediating such resistance. It also will test if our novel ERK7 inhibitor re-sensitizes cancer cells to taxane-platinum treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA222425-02
Application #
9718148
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Chen, Weiwei
Project Start
2018-08-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224