Translational Drug Discovery Group

Oncology

Summary

Despite major investment and significant advances, many cancers are poorly treated. Our approach to tackle this problem is to exploit the world-leading knowledge within the Genome Damage and Stability Centre at the University of Sussex to target DNA damage repair pathways. We believe that these pathways offer the potential for us to discover a new generation of targeted cancer chemotherapeutic agents which will be better tolerated and more effective than existing therapies.

 

Detailed Description

With more than 3.2 million new cases and 1.7 million deaths each year, cancer remains an important public health problem in Europe despite the major investment in cancer therapeutics. Given the strong association between cancer risk and age, the demographic changes in Europe with an ageing population will lead to a major increase in the cancer burden, even if age-specific rates remain constant.

Identifying treatments that specifically target cancer cells with minimal impact on normal proliferating cells remains the overriding goal of cancer research. The development of the hallmark traits of cancer involves a range of mutational events that variously activate oncogenes and disable tumour suppressor pathways that together confer viable dysfunction of the central regulatory networks of the cell. The ability of a single cell to acquire the multiple genetic changes that confer these hallmark traits depends on loss of genetic stability early in the tumour cell lineage. This is typically initiated and/or tolerated by defects in the DNA damage response.

Our research activities in oncology are focussed exclusively on exploiting the world-leading expertise and knowhow developed within the Genome Damage & Stability Centre at the University of Sussex to directly target DNA repair pathways. We are running a number of multi-disciplinary early stage drug discovery and target validation projects across the Translational Drug Discovery Group in collaboration with experts in the underpinning biology, structural biology and clinical setting.

Synergy

Most cancer cells have DNA damage repair defects and our underpinning hypothesis shares the view that a key difference between tumour and normal cells will lie in the behaviour of the complex networks of DNA damage repair pathways. This means that cancer cells could be specifically targeted by drugs or drug-combinations that exploit these intrinsic differences. Thus, if we can identify aberrations in DNA damage repair pathway functions in tumours, we can use our deep understanding of these pathways to identify novel targets, either, in the aberrant pathway, or, in a second pathway with which it shows synthetic sensitivity to cell growth or genotoxic drugs. This will allow the development of a new generation of highly tumour-specific drugs and therapeutic strategies.

Synthetic sensitivity presents a particularly attractive approach to tumour targeting, best illustrated by the lethal effect of pharmacological disruption of single strand break (SSB) repair by targeting poly-ADP-ribose polymerase (PARP1) in homologous recombination (HR)-defective tumours 7. Such tumours arise, for example, from cancer-associated defects in the DNA damage repair proteins, BRCA1, BRCA2, PALB2. Ordinarily, endogenous SSBs that escape repair by the PARP1-associated SSB repair pathway can give rise to double-strand breaks (DSBs) during replication. Whilst the elevated level of DSBs in PARP-1-inhibited cells are tolerated in cells in which DSBs can be repaired by HR (i.e. in HR-proficient cells), it has been proposed that these SSBs are lethal in HR-deficient tumour cells such as those lacking BRCA1,BRCA2, or PALB2. While the selective lethality observed in the HR-deficient tumour cells by PARP-1 inhibition is the most established example of synthetic sensitivity/lethality, our experience in dissecting DDR pathway interactions in model organisms and cell systems suggests that there will be many opportunities to exploit this concept for significant synthetic sensitisation of tumours with other genetic profiles. We propose that combining an inherent defect in one DDR pathway with pharmacological inhibition of a second (and potentially a third) DDR pathway will severely impair tumour proliferation and survival, thus enhancing therapeutic index. The expected outcome of enhancing tumour selectivity through these approaches would be to produce a wider therapeutic index and an improved clinical outcome. This will be particularly important for patients who are presenting with multiple co-morbidities.

Oncology 2