DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase I as a Novel Therapeutic Target for Ovarian Cancer Treatment
Abstract
Ovarian cancer is the most lethal gynecological cancer in the United States, affecting military Service members, their families, and the civilians they protect. Although patients with ovarian cancer initially respond to therapy, recurrent ovarian cancer is common. Relapse disease is often non-responsive to the second round of treatment, with a 5-year survival of only ~30%. Moreover, long-term survival has not improved over the last two decades. Thus, the development of new medicines is critical for the treatment of this lethal disease. Efforts to identify new drug targets (such as proteins selectively required for ovarian tumor cell growth), to develop new agents that inhibit the function of these proteins, and to increase our understanding of how ovarian cancer cells become resistant to chemotherapy drugs are essential to advance the clinical treatment and cure of ovarian cancer. In addition, recent genomic studies suggest that ovarian cancer is actually different cancers that simply share a common anatomical location, yet exhibit distinct responses to therapy. For example, triple-negative breast and renal cancers share genetic characteristics with ovarian cancer and poise similar challenges in the development of effective treatment options for patients with these diseases. These challenges are all priority points in the mission of Ovarian Cancer Research Program (OCRP) and will be addressed by the research proposed in this OCRP Pilot Award. To begin to address these clinical challenges, we have identified a novel drug target for the treatment of ovarian cancer. This protein is Tyrosyl-DNA phosphodiesterase I, or Tdp1, which plays a role in repairing damaged DNA. What is unique about Tdp1 is that is becomes covalently attached to the DNA as it removes the lesion linked to the DNA end. In other words, Tdp1 simply replaces the adduct on the DNA with itself, before liberating itself to yield a free DNA end. The formation of this Tdp1 protein-DNA complex poises a significant risk, as it is also a form of DNA damage that can lead to cell death. Our studies indicate that this protein is expressed at high levels in ovarian cancer cells, yet is present in much lower levels in normal ovarian tissue. Thus, Tdp1 constitutes an interesting drug target, yet, to date, no inhibitors of Tdp1 have been developed. We propose an innovative concept to target Tdp1, by developing small molecule inhibitors that exploit the unique mechanism of Tdp1 and actually convert this repair protein into a cellular toxin. In other words, develop drugs that increase the stability of Tdp1 linked to the DNA end and prevent the liberation of the free Tdp1 protein. Since ~50% of the ovarian tumor samples that we investigated contain increased amounts of Tdp1 compared to surrounding healthy cells, tumor cells would be much more sensitive to such Tdp1 inhibitors. Indeed, in a cell-based screen of ~150,000 compounds, ~200 were found to only induce toxicity in cells expressing Tdp1. In this proposal, we propose a drug development plan to determine and optimize the activity of the lead compounds from this screen and to determine the cytotoxic mechanisms of action of this compounds in ovarian cancer cell lines. The ultimate goal of this research proposal is to exploit the unique activity of Tdp1 in ovarian cancer in the development of a novel therapeutic regimen for the treatment of patients with primary or recurrent ovarian cancer. In addition to the development of a novel therapeutic drug, understanding the response of ovarian cancer cells to Tdp1 inhibition will also identify biomarkers of clinical response and additional drug targets for effective combinations with other therapeutics. Using cutting-edge technology (RNAi based methods), we will identify proteins that either stimulate Tdp1-dependent toxicity or confer resistance to Tdp1 inhibitors. The short-term impact will include understanding how cancer cells respond to Tdp1-dependent
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510198
Entities
People
- Robert Van Waardenburg
Organizations
- United States Army
- University of Alabama at Birmingham