FXR1 Therapy Development for Cancer Treatment

Project Summary:

Ovarian cancer is among the top-10 most fatal cancer types in Wisconsin. Mutations in breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) are major risk factors for developing ovarian cancer. Notably, women from African and Latin American racial backgrounds, who comprise ~8% of the Wisconsin population, have a higher prevalence of ovarian cancer-causing BRCA1/BRCA2 mutations. Therefore, there is an urgent need for novel drugs to treat ovarian cancer patients and address racial ovarian cancer disparities in Wisconsin.

This project team recently found that the ‘Fragile X Mental Retardation Related homolog 1 gene' (FXR1) protein is overexpressed in ovarian cancer and predictive of poor cancer patient survival. They also found that FXR1 enhances the actions of other proteins that drive cancer growth and spread. Although they and others have targeted FXR1 in cancer and other diseases through genomic approaches that reduce FXR1 protein levels (e.g. CRISPR), no small molecule drugs have been developed to directly block FXR1 activity in cancer. FXR1 contains key regions called Tudor domains critical for cancer-promoting activities.

This project will use the novel drug development pipeline that the team has implemented in the Program in Chemical Biology at the Medical College of Wisconsin to discover new drug-like compounds that bind to FXR1 Tudor domains to block FXR1 cancer-promoting activities. The team will test these compounds in cell and animal models of ovarian cancer to understand how FXR1 inhibition affects the activities of the FXR1-enhanced proteins that drive ovarian cancer growth and spread. Successful completion of this project will result in selective and effective new drug-like compounds that slow the growth of ovarian cancer by blocking the cancer-promoting activities of FXR1. This is an essential first step toward first-in-class FXR1 drugs to treat ovarian cancer patients and help address ovarian cancer disparities in Wisconsin.