Drug Design, Cancer & Toxicity Current Activity
General Introduction
The DDCT theme encompassing a broad range of research activities, which range from pure biological research attempting to understand how the human body functions to cutting edge clinical studies helping to translate these basic findings into enhanced clinical practice.
Four current highlight areas are described below, but for a wider overview of our areas of research please also visit our Podcast and Highlight Publications pages.
Multiple Drug Resistance and Cancer
Long-term (chronic) exposure of people to therapeutic medicines can result in alterations to the body, such that they no longer respond effectively to the treatment. Such drug resistance is a major issue with the treatment of many complex diseases, such as cancer, and can often lead the need to switch to alternate therapies, if such exist. The potential mechanisms of multiple drug resistance are many, and understanding these is an important first step in developing effective treatments, ensuring long term health and wellbeing for everyone.
In collaboration with the Royal Surrey County Hospital, Section of Gynaecological Oncology, Helen Coley has been involved in translational studies into drug resistance in ovarian cancer. Recent laboratory-based studies using novel drug resistant human ovarian cancer cell lines have identified a number of genes that are differentially altered in their expression levels as a consequence of drug resistance.
This approach is designed to help identify markers of response to treatment with chemotherapeutics, and may help to predict those patients who are more likely to benefit from treatment with a particular drug.
Systems Modeling of Biological Networks
For the body to produce the most efficient response to any chemical challenge, multiple biological systems may need to be activated, and it is the co-ordinated action of all of these systems that produces the ultimate response. Hence, examining any one of these systems in isolation may be insufficient to understand the total network, as novel properties will emerge when all the individual systems work together in a coordinated network
We are using deterministic models to reproduce these regulatory signal networks in silico, and then using them to both understand the design principles behind these networks and as tools to aid in extrapolation of data from one scenario to another.
Understanding these networks will allow us to better predict body responses, which will aid in the improved risk assessment of drugs, as well as aiding development of novel therapies.
Metabolomics Studies on Drug Action
Metabolomics refers to analysis of the metabolome, i.e. the total collection of metabolites in a cell, tissue, or organism, to identify changes in metabolic pathways that can be used to better understand biological mechanisms related to health and disease. We have focussed on the identification of endogenous metabolites and pathways that are perturbed by xenobiotics, e.g. the glycolysis and citric acid cycle, as well metabolism of the xenobiotics themselves, e.g. troglitazone.
We use cell culture, followed by LC-MS to separate and identify metabolites. Multivariate statistics are then used to identify components of interest, which can then be taken on for further analysis.
Targeting HOX genes in Cancer (Cancer Research theme page)
The HOX genes are a family of genes that encode transcription factors that control gene expression in many animals. These HOX proteins regulate the expression of many important genes involved in the growth and development of tissues, and their dysregulation can result in the development of many diseases, including cancer.
We are interested in the role of transcriptional regulation in cancer, especially from the view point of using transcription factors as therapeutic targets and / or biomarkers. Current projects involve targeting a family of transcription factors known as HOX genes. These help to define the identity of cells and tissues in early development but they are also expressed in cancer cells. Our research has shown that targeting HOX genes with a novel peptide, HXR9, can kill cancer cells whilst sparing normal adult cells.
In addition, we are studying the use of another transcription factor, EN2, as a potential biomarker for prostate cancer. We use a broad range of techniques including micorarray, QPCR, specialised cell culture techniques for culturing primary tumours ex vivo, and a number of specialised animal models for cancer.
