Enhancing Immune Checkpoint Blockade by Reprogramming the Methylome with Novel Epigenetic Modulators That Induce a Proinflammatory Response
Abstract
This project addresses one of the FY20 LCRP Areas of Emphasis: “Identify innovative strategies for the treatment of lung cancer.” This proposal will lay the groundwork for an entirely new approach to lung cancer treatment. Lung cancer is the second most common cancer in American women and men, 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. New treatments for lung cancer are urgently needed because conventional chemotherapy only extends survival for a very short time, and even advanced immunotherapy only benefits about 20% of patients. Mutations in the DNA (A, C, G, T building blocks are jumbled) are well known to cause cancer. However, when we used a different method to look at a database containing information about the DNA of many lung cancer patients, we discovered that many patients showed a new defect in a chemical modification to their DNA. The problem is that a chemical modification to the cytosine (C) building block is missing. This chemical modification normally creates methylated cytosine (mC), which is a signal to turn off the expression of genes. The DNA of these lung cancer cases have low mC, which means genes that are normally turned off are turned on. Importantly, the low mC are at a large number of cancer-causing genes, and thus turn them on. In addition, low mC cause cancer cells to not respond to immunotherapy. From this analysis, we hypothesize that low mC is responsible for abnormal expression of pro-cancer genes and genes that block immunotherapy. Low mC is a new type of defect that is not a common genetic mutation in A, G, C, T, but occurs at what is known as the “epigenetic” level. Epigenetics is basically a new layer of code within the DNA code. Our proposal is to develop new drugs that can fix problematic epigenetic code. TDG is an enzyme that cause low mC levels, and our published results have shown that, if we inhibit TDG melanoma cells (a skin cancer) cannot grow. We know that blocking TDG will increase mC and shut off the pro-cancer genes and the immunotherapy resistance genes. This is proof of principle that TDG is a new anti-cancer drug target that should be developed for treating cancer. Realizing this goal would provide the first-in-class epigenetic drug that works by turning off genes that cause cancer. This will complement existing epigenetic drugs that work by turning on genes that stop cancer growth. Our laboratories have just identified the first chemical inhibitor of TDG. This “lead” compound basically shows that TDG is a druggable target and that it has the potential to restore mC to genes that have low mC. Importantly, our laboratory studies showed that this TDG inhibitor can stop lung cancer cells from growing. In this project, we propose to study how our TDG inhibitor blocks lung cancer cell growth because this knowledge will provide new information to improve therapy. We will also use an innovative laboratory method to test our hypothesis that the TDG inhibitor will improve killing of lung cancer by immunotherapy. The ultimate application of our studies will be the development of new, “intelligent” drugs that block TDG that is overactive in patients; this may take 5-7 years. Importantly, we will be developing a completely new kind of cancer drug that currently does not exist.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110648
Entities
People
- Alfonso Bellacosa
Organizations
- United States Army