Title: Targetting WW domain function in ubiquitin ligases overexpressed in prostate cancer
Funder: Prostate Cancer UK

Abstract: What are you proposing? WWP2 is a protein involved in signalling inside the cell. It interacts with three other proteins to determine if the cell will multiply or not, using regions called WW domains. All of those binding partners are involved in tumour progression and metastasis, and an increase in WWP2 itself can cause tumour cells to become more aggressive. Dr Chantry’s research shows that activating WWP2 can make cells multiply faster, and that the distribution of WWP2 proteins in prostate cancer cells is different from normal tissues. We are proposing that we can now develop new blocking drugs that prevent WWP2 from coming into contact with its targets inside cells, and use this approach as a new way to prevent the onset and spread of prostate cancer. Why are you proposing it? At present, current treatments for prostate cancer involve a combination of radiotherapy and chemotherapy. Whilst there are many examples of successful treatment outcomes using these approaches, there are often many adverse side-effects and long-term complications associated with chemotherapeutic resistance. In this project, we aim to focus on a new molecular target that we have discovered inside prostate cancer cells. Here, we will use the detailed information we have gathered about the way this protein works in order to selectively block its attempts to actively destroy other cellular proteins that normally suppress tumour growth. We strongly believe that this will lead to new treatments for prostate cancer. How are you proposing to do it? We have already identified a small molecule that blocks the action of WWP2 and prevents processes associated with prostate cancer progression when incubated with cancer cells in vitro. We would now like perform experiments to improve the delivery and efficiency of this peptide by making and testing equivalent derivatives. In addition, and in support of this important aim, we will use a technique known as NMR spectroscopy to understand how WWP2 interacts with all of three of its known targets. We will map the regions of the proteins involved, at a detailed molecular and atomic level. We will then use this information to design additional peptides to specifically prevent interactions between WWP2 and each of its targets. We will test the effect of these peptides on cancer cells, so that we can design the best possible combination of peptides that provide maximum effect against prostate cancer cell growth and spread. How long will it take? 36 months What are the expected outcomes? The key outcomes of this study will be the elucidation of an important new druggable target, and development of new treatments. We are a dedicated team of experienced research scientists and work closely with local Clinical Oncologists. Fortunately, at UEA Norwich, we are also undergoing a major expansion in our Clinical Research Facilities with a £19million new investment in a state-of-the art Research Institute with a strong emphasis on prostate cancer. We are therefore well placed to deliver real outcomes from our project with great potential for improving understanding and treatment of prostate cancer. How could it make a difference to the lives of men affected by prostate cancer? One of the big challenges for prostate cancer research is to capitalize on important laboratory studies on disease mechanisms, and to translate this information into real benefit for patients. The importance of this study is that it begins to bridge this gap and have a direct and immediate impact on men affected by prostate cancer by providing new insight into how proteins found in the prostate normally prevent the onset and progression of prostate cancer. Importantly, as the project progresses, we will also be in a strong position to design new molecules that can be developed further as treatment options. Please write a summary of the project in one sentence only. We will develop a new set of drugs that block a very destructive enzyme inside prostate cancer cells that we and others have shown is responsible for eliminating our main natural defences against prostate cancer growth and spread.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS