Translational approaches to improving cancer screening and diagnosis

As we understand more about how tumours arise, it should be possible to devise better strategies to diagnose and treat cancer. We are aiming to develop more effective ways to detect common malignancies, through an understanding of the biology of cancer cells. We are currently analysing a test that we have developed to improve diagnosis of cancers at a number of sites in the body, including cervix, mouth and bowel. For the first two cancers we are working in collaboration with colleagues in Bangalore, India. In addition, we are investigating the mechanisms by which some types of human papillomavirus, the wart virus, cause cancer in the genital tract, particularly the cervix. We are studying the process by which fragments of the virus are inserted into the DNA of infected cells, as well as the significance of changes in the levels of cellular genes that are associated with the development of malignancy. This work may lead to methods to predict how aggressive a particular tumour will be, so that each patient receives neither too little nor too much treatment, and may also suggest new strategies for treating the disease.

We aim to: (i) use minichromosome maintenance proteins (MCMs) as biomarkers to improve cancer screening and (ii) study mechanisms of human papillomavirus (HPV)-associated carcinogenesis, in order to develop more effective prognostic and therapeutic interventions for cervical cancer, an epithelial malignancy of major global importance. We demonstrated the clinical value of MCM immunocytochemistry in improving the early detection of several common malignancies, including cervical, colorectal and lung cancer. The first clinical product is now in use internationally and a second generation version is in major FDA trials. We use a unique preclinical model of HPV-related carcinogenesis, validated through a large tissue resource, to study relationships between viral and host factors in the early stages of the cervical metaplasia-dysplasia-carcinoma sequence. As part of this work we discovered the role of two genes that are frequently over-expressed in cervical cancers and will study the potential of one of these, the cytokine receptor OSMR, to act as a cell surface target for antibody-based inhibition. We will further investigate the mechanisms by which HPV oncogene expression is deregulated during cervical carcinogenesis and study the significance of viral physical state (episomal vs. integrated) and site of integration into the host genome, as well as mechanisms of HPV persistence in cervical epithelial cells. We aim to develop new tools for diagnosis and treatment at different stages in the lengthy progression sequence from HPV infection to malignancy. Important clinical benefits of this work will be reduced morbidity and costs associated with over-treatment of non-progressive cervical pre-cancers and improved therapeutic options in cervical carcinomas, particularly early-stage disease.