Sussex Drug Discovery Centre (SDDC)

Oncology

Despite major advances in the understanding of tumour biology, and the significant investment in therapies that target the hallmarks of cancer, many cancers remain poorly treated. While for some patients targeted drug treatments result in extended periods of cancer remission, other patients with a seemingly similar diagnosis remain unresponsive, limiting the average life extension of expensive drug treatments to a matter of months.

Genomic instability is inherent to the evolution of tumours. The ability of a single cell to acquire the multiple genetic changes that confer the hallmarks of cancer depends on loss of genomic stability early in the tumour cell lineage. While defects in genome maintenance and repair provide tumours with the capacity to mutate, these same defects result in an increased sensitivity to further erosion of DNA repair mechanisms and provide an opportunity to selectively target cancer cells with minimal impact on normal proliferating cells. Harnessing the world-leading knowledge and discoveries within the Genome Damage and Stability Centre at the University of Sussex, we are targeting DNA damage repair pathways to discover a new generation of targeted cancer chemotherapeutic agents that will be better tolerated and more effective than existing therapies.

Drugs that regulate DNA repair pathways can act in concert with current genotoxic therapies by potentiating their effects, or as single therapy approaches by exploiting deficiencies in DNA repair pathways in synthetically lethal combinations. 

 

Understanding genome stability can deliver better tolerated and more efficacious medicines

Despite advances in targeted therapies, the mainstay of cancer chemotherapy are genotoxic treatments that damage the DNA of tumour cells. Large investments have been made in the delivery of targeted radiotherapy as an effective approach to damage the DNA of highly proliferating cancer cells.

Tumour cells can respond to genotoxic agents and ionising radiation by the upregulation of DNA repair pathways which can minimise the effect of DNA damaging agents resulting in a loss of efficacy and resistance. In collaboration with Genome Damage & Stability Centre GDSC at the University of Sussex  we have identified targets in DNA repair pathways that would potentiate the effects of DNA damaging agents while sparing toxic side effects on normal cells.  In the Sussex Drug Discovery Centre we are running a number of multi-disciplinary early stage drug discovery projects in collaboration with experts in the underpinning biology, structural biology and clinical setting, to identify novel tool compounds that can be used to further validate this concept.

 

Synthetic lethality offers an exciting opportunity for targeted medicines

Synthetic lethality presents a particularly attractive approach to tumour targeting. In the absence of genotoxic drugs, the DNA in normal proliferating cells is continuously being damaged and repaired. It is estimated that as many as 100,000 DNA lesions occur in each cell every day. Pathways that repair DNA in tumour cells are frequently defective – this is the reason why they can readily mutate as the DNA repair is prone to error - but loss of a second gene function within the same or related pathway cannot be tolerated by the tumour cell, as many DNA breaks remain unrepaired. For cells that are proliferating, the result of unrepaired breaks in DNA is cell death.

The power of next generation gene sequencing is enabling the identification of the gene mutations that drive cancer. In many cases the key mutations are in genes that have important roles in maintaining genome stability. In collaboration with colleagues in the GDSC we are identifying synthetically lethal gene combinations using specific gene knockdown studies in tumour cell lines. Together with the experts in the underpinning biology, scientists in the Sussex Drug discovery centre are developing small molecule inhibitors of these drug targets to be used as tool compounds to help validate the synthetic lethality concept in pre-clinical models.

 

Clinical Applications of Synthetic lethality

The concept of synthetic lethality has been validated in the clinic with approval for the use of Olaparib in ovarian cancer. Such tumours arise from cancer-associated defects in the DNA damage repair proteins, BRCA1, BRCA2 & PALB2. Germline or somatic mutations in these proteins lead to a loss of function that causes error prone DNA repair and the development of new gene mutations that drive the cancer. While BRCA1, BRCA2 & PALB2 mutant genes can predispose a patient to cancer, they are also the Achilles heel of the tumour cell. Inhibition of the enzyme poly-AP-ribose polymerase (PARP1) reduces further the capacity of the tumour cell to repair its DNA, leading to many double strand breaks in the DNA and ultimately cell death. While the selective lethality observed in the HR-deficient tumour cells by PARP-1 inhibition is the most established example of synthetic sensitivity/lethality, current work 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. Enhancing tumour selectivity through synthetic lethality has the potential to develop effective chemotherapeutic approaches with a wider therapeutic index and an improved clinical outcome. This will be particularly important for patients who are presenting with multiple co-morbidities.