Infection is a major cause of cancer worldwide. Viruses are associated with ~15% of human cancers, which approximates to about 2 million new cases very year in the world. Research in the the Whitehouse laboratory aims to understand how viruses cause cancer and develop novel antiviral staratgies to prevent infection and tumourigenesis. We focus on studying the molecular biology of the two most recently discovered human tumour viruses.
(i) Kaposi's sarcoma associated herpesvirus (KSHV)
This is an oncogeneic herpesviruses which has been associated with a variety of lymphoproliferative disorders including Kaposi's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. Widespread HIV infection has now turned KS into an epidemic disease in Africa. KS is now the most common adult tumour in parts of Africa. Like other herpesviruses, KSHV has two distinct forms of infection, latency and lytic replication. Although latency has been implicated in tumourigenesis, reactivation and lytic replication play an important part in the pathogenesis and spread of KSHV infection. Therefore, we have a major research focus to study the molecular mechanisms which regulate reactivation and lytic gene expression to provide a better understanding of KSHV pathogenesis. Moreover, these projects will provide valuable information on the host cell-virus interactions which may ultimately lead to the identification of specific antiviral targets which could be developed as novel treatments for this important human pathogen.
(ii) Merkel cell polyomavirus (MCPyV)
Merkel cell carcinoma (MCC) is a highly aggressive human cancer of the skin that occurs in elderly and immunosuppressed patients. Merkel cell polyomavirus was discovered in 2008 and is present in 80% of human Merkel cell carcinomas. Therefore, MCPyV is likely to have a causative role in MCC. Due to its recent discovery, little is known about the link between MCPyV and MCC. Therefore, we are currently investigating the role of MCPyV encoded proteins in transformation and immortalisation of human cells.
1. Identification of essential virus-host cell interactions which are required for virus replication or transformation.
We are utilising a range of cutting-edge transcriptomic and quantitative proteomic approaches to globally identify how viral proteins affect the cellular environment. These interactions can then be verified using biochemical and con-focal imaging techniques. This is helping to identify essential virus-host cell interactions which we can target by novel antiviral strategies to inhibit virus replication and transformation.
We are particularly interested in virus-host cell interactions which
i. Regulate reactivation in Kaposi's sarcoma associated herpesvirus
ii. Regulate virus RNA processing
iii. Immune evasion strategies employed by oncogenic viruses
iv. Virus-host cell interactions required for the aggressive metastatic potential of some virus-induced cancers
2. Structural-based rational drug design approaches to inhibit oncogenic viruses.
To date, there are limited antiviral strategies for oncogenic viruses. Although vaccines have been developed for a few of these viruses, these are not available for all the 7 oncogenic viruses, incluing KSHV and MCPyV. Therefore novel antiviral straetgies are required to combat these important human pathogens. Upon identification of essential virus-host cell interactions using transcriptomic and quantitative proteomic approaches, we utilise a structural-based rational drug design approach to molecular model and design small molecules to inhibit these interactions. Virtual high-throughput screening campaigns are conducted from a large libraries of commercially available compounds. Docking routines and ligand-similarity searches are utilised to design compounds which have the potential to inhibit these essential virus-host cel interactions. Once the virtual high-throughput screening campaign has been performed selected compounds are then assessed in virus-based assays for antiviral activity.
Research is currently funded by BBSRC (PDRAs and PhDs), MRC (PDRA and PhDs), Worldwide Cancer Research (PDRA), Rosetrees Trust (PhD) and Wellcome Trust (PhD).
A list of recent publications from the laboratory are listed at Recent publications