Genetic information is contained in units of DNA in a cell called chromosomes. Normal cells rely upon checkpoints to control the passage of genetic information contained in chromosomes to daughter cells. The mitotic checkpoint, regulates the passage of genetic information before the formation of daughter cells and if this fails, cancers become resistant to death induced by the taxane breast cancer drug and develop resistance to other cancer drugs in the laboratory. Failure of the same checkpoint promotes gain or loss of whole chromosomes (called chromosomal instability, CIN cancers) associated with worse prognosis in cancer patients. Many patients with breast cancer experience side effects but derive limited or no benefit from taxane treatment. A CR-UK team will analyse breast cancer tissue from patients treated with taxanes within clinical trials to assess whether CIN is associated with taxane resistance. This may identify which patients may benefit from this treatment in the future. The CRUK team will identify how to selectively target CIN cancers to promote new approaches for anticancer drug discovery. These drugs may eventually limit the evolution of tumour drug resistance and have greater cancer-specificity, reducing side effects to normal tissue (skin, hair and white blood cells) with normal chromosome number.

Have you ever wondered why your hands are the size they are? Or why some people have bigger hands, but they are almost identical in shape and proportion to your hands? The control of organ growth is highly complex, but highly important, as when the control system fails, we get overgrowth, and frequently cancer. How does the organ know when to stop growing? How does it control its shape? If we can understand this, perhaps we will be able to understand what happens when tissues over grow, and treat the problem (e.g. cancer) at its source. Many biologists have successfully used the Drosophila wing as a model to study growth control, revealing many parallels to human growth control. I hope to put all these data, the pieces of a puzzle, together, into a mathematical/computer model and eventually make a virtual wing. I‘ll be able to compare the relative importance of the different control mechanisms, something that‘s quite hard to do via experiments. I may find that internal control is key, and the environment plays little role, or vice versa. I can also model different cancerous conditions, and quickly test treatments before deciding whether they are worth trying experimentally/clinically.

To achieve productive infection, HIV must insert a DNA copy of its genome into a chromosome of a human cell. This process is orchestrated by integrase, an enzyme carried by the virus. Once integration is complete, the viral genome becomes a permanent resident in the cell. From there it will initiate production of new infectious particles or it might stay dormant and undetected for a long period of time. Integration is partly responsible for the persistence of HIV infection. Yet, the dependence of HIV on integration is also an exploitable weakness. A new class of antiretroviral drugs disrupts enzymatic activity of integrase taking advantage of this weakness to fight HIV. The main impediment to the development of these drugs, also known as integrase inhibitors, is our limited understanding of the structural aspects of HIV integration. In 2010 we determined the long-sought after three-dimensional structure of retroviral integrase bound to viral DNA ends. For these studies we chose to use IN derived from prototype foamy virus (PFV), which is much more soluble and active when removed from its natural environment compared to most of other retroviral INs. On the other hand, all retroviral integrase enzymes are very similar in their structural makeup. Therefore, although PFV is not a human pathogen, its integrase is an ideal model for experimentation as a proxy for HIV integrase. Crucially, it already allowed us to explain how HIV integrase inhibitors work. The current project aims use the unique biochemical properties of PFV integrase to understand the retroviral integration process down to a fine detail. Using X-ray crystallography as our main tool, we will determine three-dimensional structures of PFV integrase at various stages of the integration process. Furthermore, taking advantage of its similarity to HIV integrase, we will use it to understand how HIV can sometimes evade the action of integrase inhibiting drugs. We will also generate more structural information that drug developers will use to improve potency of integrase inhibitors. Our data will be of substantial value for drug discovery and development by both academic and private groups and will serve to reduce the costs and improve availability of the eventual treatments.

For many patients standard chemo- and/or radio-therapy treatments for cancer are not curative and are associated with significant side-effects. Using viruses to treat cancer is an example of the newer biological therapies being developed. Viruses can be modified to multiply in cancer cells at much higher rates than in healthy cells, producing a wave of infection that spreads through solid tumour deposits and destroys them (a process called oncolysis). To date there have been around 30 clinical trials using oncolytic adenoviruses in patients with cancer. While the side effects even with large doses of virus are fairly mild, the success rates have been variable. One of the limitations to viral therapy is the patient‘s immune system that quickly recognises the virus as foreign and starts to remove it from the tumour before it has had a chance to cause significant tumour-cell death. The project that I propose to undertake is to investigate the interactions between the host immune system and the oncolytic adenovirus. The ultimate aim is to develop a way of modifying the patient‘s immune response to minimise its detrimental effect on the virus thus enhancing the virus anti-tumour potency.

To achieve productive infection, HIV must insert a DNA copy of its genome into a chromosome of a human cell. This complex process is orchestrated by integrase, an enzyme carried by the virus. Once integration is complete, the viral genome becomes a permanent resident in a cellular chromosome. From there it will initiate production of new infectious particles or it might stay dormant and undetected for a long period of time. The integration is partly responsible for the notable persistence of retroviral infections. Yet, the dependence of HIV on integration is also an exploitable weakness. A new class of drugs, disrupting enzymatic activity of integrase, called strand transfer inhibitors, takes advantage of this weakness to fight HIV infection. The three-dimensional atomic structure of HIV integrase is not known and even less understood is the architecture of its active form during integration process. Currently, the lack of structural information is the major impediment to the development of strand transfer inhibitors. This project aims to elucidate the three-dimensional structure of integrase. We will determine atomic structures of this protein separately and in active, DNA-bound, form. To achieve our goals we will use X-ray crystallography, which allows visualization of protein molecules, although requiring a significant amount of preparatory work. In particular, to determine high-resolution structures, we will have to obtain crystals of integrase in complex with accessory proteins and/or DNA. Our results will be published in open access journals and the data will be accessible to the scientific community via public databases. Our research will generate dat, which will be of great value for drug discovery by both academic and private groups, and will serve to reduce the costs and improve availability of the eventual treatments.