NUDT5 as a Novel Target for Ovarian Cancer
Abstract
Ovarian cancer is a devastating disease; even though chemotherapy treatments can be initially effective, this cancer recurs in over 80% of cases, so the majority of patients do not live beyond 5 years past their initial diagnosis. A primary reason for disease recurrence is that cancer cells develop resistance to common chemotherapy drugs, such as platinum-based chemotherapies and PARP inhibitors, so treatments become ineffective, and cancer cells in the patient continue to spread, eventually reaching distant areas of the body. If we could block the spread of tumors, we could prevent the deaths of thousands of ovarian cancer patients each year. To block the spread of tumors, we need to identify a novel target: a specific gene or protein that when blocked or inhibited can reduce or even eliminate the growth and spread of ovarian cancer. Our previous work has identified the potential target gene for ovarian cancer, NUDT5. Our preliminary data reveal that NUDT5 levels are higher in ovarian cancer tumors compared to normal tissues, and ovarian cancer patients with higher NUDT5 levels have worse survival rates. NUDT5 has already been linked to the cancerous behaviors of breast cancer cells. Since NUDT5 also contributes to repairing DNA and PARP inhibitors kill tumor cells by enabling more DNA mutations, NUDT5 has exciting potential to make ovarian cancer cells more sensitive to existing PARP inhibitor treatments and, therefore, result in less toxic, more-effective treatment strategies. The goal of this proposed work is to explore the potential of NUDT5, which we have recently identified through our previous OCRP Pilot Award as a gene to target for novel drug development to stop ovarian cancer progression. Our approach is based on our previous discovery that platinum-resistant cancer cells are softer, or more deformable, than their drug-sensitive counterparts. Using a novel technology that we recently invented to measure cell deformability across large numbers of cell samples, we identified the potential novel candidate gene NUDT5. This candidate gene contributes to cellular energy production, which is important for cells to survive mechanical challenges of metastasis and to repair DNA damage. Our preliminary data show that NUDT5 is expressed at higher levels in ovarian cancer patients that have poor survival. We also have preliminary data that shows blocking NUDT5 makes ovarian cancer cells less invasive, which is required for their spread and metastasis. For all of these reasons, NUDT5 shows promise as a target for ovarian cancer. In the proposed research, we will determine how NUDT5 contributes to ovarian cancer progression and metastasis. We will test blockade of NUDT5 to reduce ovarian cancer metastasis using in vitro and in vivo models. To define how targeting of NUDT5 impacts the progression of ovarian cancer, we have assembled a multidisciplinary team that consists of a biophysicist and engineer who is an expert in understanding cells as materials; an ovarian cancer biologist who is an expert in developing mouse models of ovarian cancer that have well-defined genetic mutations and show similar spread as human ovarian carcinomas; experts in imaging the structure of DNA in the nucleus; and an ovarian cancer patient advocate who will ensure our project will meet the needs of ovarian cancer patients for more effective and less toxic treatment options. Following this proposed project to test NUDT5 in mice, future experiments could test blocking NUDT5 in ovarian cancer patients in a clinical trial. If we are able to decrease the spread of ovarian tumors by blocking NUDT5, other treatments could become more effective in eradicating existing tumors. Better treatments could also mean higher rates of remission, increased survival, and improved quality of life for more patients. Ovarian cancer patients face the reality that their prognosis is a 5-year survival rate after initial diagnosis. In 2019, the est
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210354
Entities
People
- Amy Rowat
Organizations
- United States Army
- University of California, Los Angeles