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Head and neck (HN) cancers are those that affect areas inside the head and neck region, for example inside the mouth, nose, and throat. Although publicly less well known than lung cancer, these cancers are also very clearly associated with the consumption of tobacco-products, including cigarettes as well as smokeless tobacco. With an estimate of almost 60,000 new cases in the United States during 2015 alone, these cancers pose a significant burden on public health. Treatment of HN cancers is not easy, with only 45-50% of patients surviving for longer than 5 years after diagnosis. Most cancers are caused by changes (mutations) in the blueprint (genes) for human cell parts (proteins) that result in unconstrained cell division. However, a portion of HN cancers is caused by infection with a virus called Human Papillomavirus (HPV), which is the same family of viruses that also causes cervical cancer. Patients with this subset of HN cancers generally have better treatment outcomes, with almost 75-80% surviving for longer than 5 years after diagnosis. This difference in response to treatment of a similar disease is not well understood. My proposal aims to close this knowledge gap by comparing these two different types of HN cancer. Because viruses are very small, they rely on the help of human parts (proteins) for successful propagation. Viruses that cause cancer often do so by interacting with proteins that are found to otherwise be faulty (mutated) in cancers caused by different means, e.g. tobacco-smoking. HPV for example has been shown to use one of its own viral proteins (called E6) to bind and inactivate a human protein (p53), which is also commonly inactivated in cancers. I hypothesize that this is not an isolated case, and that by looking at which other proteins the virus binds, we can learn more about which proteins of the human cell are targeted during the development of cancer. The scientific community has put a huge effort into cataloging all changes within different types of cancer as compared to normal cells. This wealth of data is publicly available, yet the direct conclusions that we were able to draw from it have been unsatisfactory so far. It seems that only the most common changes are shared between the majority of patients, whereas many more "rare" changes seem to lead to the final disease. In this project I plan to combine the strengths of these two different types of data: how HPV interacts with the human cell, and which parts of cells are changed in head and neck cancer. For this, I will first determine the interactions of a specific type of HPV (HPV-16, the strain found in most HPV-positive HN cancers) with human cells. I will compare "normal" cells with those that resemble HN cancer caused by smoking. Then, I will compare this data with the publicly available changes found in HN cancers. The proteins I find to be targeted both by the virus and in tobacco-related cancers will be potential targets for novel, more specific drug development. In order to confirm these hits, I will perform experiments to investigate the consequences of the changes when they are introduced into "normal" cells. I will also focus on specific targets and investigate their mechanism of action in more detail. In preliminary work performed for this project, I have identified an exciting lead that suggests my proposed methodology will work. I found the HPV protein E1 to bind to a human protein, called KEAP1. This protein is changed in more HN cancers that are not caused by HPV, thus fitting the pattern I described above. KEAP1 plays an important role in human cells, where it helps to keep the response to certain chemicals in check. If it is lost or faulty, the response can go awry and cause the cell to be more prone to dividing uncontrollably, which is a critical step on the way to becoming cancerous. As part of this proposal, I will follow up on this promising connection. As shown by this example, my strategy has the potential to reveal new targets for drug development to stop head and neck cancer, and provide patients of smoking-related disease with similar treatment chances as currently only seen for HPV-associated cancers. |
