Cellular responses to DNA damage: from molecular insights to new medicines

Speaker: Steve Jackson
Department: Gurdon institute, University of Cambridge
Subject: Cellular responses to DNA damage
Location: Erasmus MC Rotterdam

Date: 27 September 2016
Author: Gabriele Kockelkoren

On average, 2×1021  lesions occur per day in each person. These lesions can be caused by errors in the replication pathway or exposure to radiation. Luckily, cells have mechanisms to repair the lesions. Different types of lesions can be distinguished: single-strand breaks (SSBs), double-strand breaks (DSBs), insertions, deletions and mismatches. These can all be repaired by different kinds of DNA repair mechanisms. Each mechanism is dedicated to the reparation of a certain lesion. In most cases the DNA is repaired rapidly and with high precision/accuracy. These pathways are very fascinating to work on, but we also know that defects in the pathways give rise to a wide range of pathology. These errors may lead to the development of cancer, premature aging, infertility or immune-deficiency. In addition to DNA repair by protein complexes, the cell reacts on the repair machinery by induction of repairing factors, transcriptional regulation, cell cycle control and apoptosis or renascence. This cascade of reaction is known as the DNA damage response (DDR).

Steve Jackson from the University of Cambridge is interested in studying the moving field of DNA damage repair, especially from a therapeutic perspective. Nowadays, the field of DNA damage and its repair is utmost interesting, as many new tools and techniques are being developed which have never been used before. These tools give us new insights in the cellular machinery and its complex behaviour. Almost 500 proteins are directly connected to the repair system. This gives in advantage in treatment for pathologies caused by defects in these pathways, as there are many druggable targets to inhibit the various DNA repair systems.

Genes work together with other genes and they are connected to the phenotypes and affect diseases. Phenotypes caused by a gene defect are strongly affected by the actions of other genes and by environmental factors. If we think about genetic interactions we see that some genes have few interactions, while others have high interactive abilities in different biological parts, while being involved in separate pathways. This gives a strong distinction between genetic enhancers (synthetic lethality) and suppressors (synthetic viability).

In 1997 Steve Jackson founded his own company, named KuDOS. The main goal of the company was to create inhibitors for the DNA repair pathways. By inhibiting the DNA repair pathways you:

  1. Enhance efficacy and reduce side-effects of radiotherapy and chemotherapy.
  2. Create selective activity on cancers by targeting differences between cancerous and normal cells.

The most promising compound which has been developed by KuDOS is a poly ADP-ribose polymerase (PARP) inhibitor called olaparib/LynparzaTM. PARP is a DNA damage activator enzyme, as PARP promotes single-strand break repair and base excision repair. By inhibiting PARP, the repair is slowed down and the PARP molecule remains trapped on the DNA. The inhibition of PARP in healthy cells for a short period is not deleterious, however cancer cells are very sensitive to the inhibition of PARP. Steve Jackson used the BRCA1 and BRCA2 mutations as an example. Cancer cells with these mutations are not able to repair DSBs and by addition of the inhibition of PARP, the cells will be exposed to too much damage. As they are not able to repair this, cell death is the final option.

jackson

Figure 1: Suppressing PARP activity prevents SSB repair via the BER pathway, but other DNA repair pathways such as HR and NHEJ simply take over. However, if PARP inhibitors are used against tumours in which there is already a DNA repair defect, the combination drives synthetic lethality. Source: http://www.onclive.com/publications/oncology-live/2013/august-2013/new-life-for-parp-inhibitors-emerging-agents-leave-mark-at-asco#sthash.Prd7k8XI.dpuf

In December 2014 the use of Olaparib has received the European and FDA approval for ovarian cancer associated with BRCA1/2. This is the first in class drug targeting PARP. KuDOS is working on other potential drugs for clinical trial.

It is very interesting to see how an idea can grow into a successful business, where it all starts in the lab. Steve Jackson also showed us the difficulties of being a scientist and proving that your method, is the one working for many patients.

 

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