Thymine DNA Glycosylase as a Novel Target for Lung Cancer
Abstract
This research project addresses the following Lung Cancer Research Program Areas of Emphasis: "Identify innovative strategies for prevention and treatment of early and/or localized lung cancer" and "Understand susceptibility or resistance to treatment." In fact, this proposal will lay the groundwork for a new approach to lung cancer treatment. New treatments for lung cancer are urgently needed because conventional chemotherapy only marginally extends survival and resistance to therapy inevitably develops. We have been studying a protein called Thymine DNA Glycosylase (TDG) that not only repairs damage to DNA, but also uses a second activity to control the expression of genes. We made the unexpected discovery that when we experimentally eliminated TDG in many cancer cells, including lung cancer, they stopped growing and died. The same thing happened when cancer cells, including lung cancer, were treated with our newly identified drugs that inhibit TDG. We have therefore demonstrated biologically and chemically that inhibiting TDG is a novel way to treat lung cancer. In addition, we have identified a biomarker in cells that shows positive response to TDG inhibitors. In this project, we will study how inhibiting TDG in lung cancer cells results in cell death because this will further provide new approaches to enhance therapy. We will also determine the cancer cell-killing abilities of TDG inhibitors alone or in combination with conventional chemotherapy drugs or so-called "epigenetic drugs" that are currently being tested in the treatment of lung cancer. The ultimate application of these groundwork studies will be the development of new, "intelligent" drugs that block TDG and are active in patients; this may take 5-7 years. Importantly, some of the TDG inhibitors that we found are already approved by the US Food and Drug Administration or foreign drug agencies, which should accelerate their use in the clinic as anti-cancer agents. In addition, our proposal will study the most active combinations of TDG plus conventional chemotherapy agents used in lung cancer, which will also facilitate future clinical trials. Not only will these studies advance patient care, but they will also represent a significant contribution to cancer research through the identification of new mechanisms of cancer cell killing that could be applied to both lung cancer and other cancers types. Lung cancer is the most common cancer in American men and the second most common cancer in American women, and the first leading cause of cancer death in both sexes. Eradicating lung cancer is important not only for the public at large, but also particularly for military personnel, given their increased risk from tobacco smoke, and occupational hazards. Our proposed research has the potential of making a great and positive impact on the treatment of lung cancer in Veterans, those in active duty, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710136
Entities
People
- Alfonso Bellacosa
Organizations
- United States Army