PARP and BRCA story
My name is Thomas Helleday and as a teenager I started working extra in the local hospital, to earn some extra bucks. Being 16 years old, I started in a haematology ward caring for leukemia patients, of which many suffered from chemotherapy side effects and often died. Being only 16 years old and never before experiencing death, it was a shocking experience seeing neighbours and even students from the same school suffer and die from the disease. I decided I wanted to find a cure for cancer.
Targeting tumour suppressors, the birth of synthetic lethal approach to kill cancer
Oncogenes drive cancer growth and have been a major target for treatments, with many successful examples. However, tumour suppressors are very commonly mutated, such as p53, and there hasn’t been any therapeutic option to tailor treatments based on the tumour suppressor gene mutation. In 1997 Nobel Prize laureate Lee H. Hartwell suggested a synthetic lethal approach for targeting the tumour suppressors (Hartwell et al. 1997 Science, 278,1064–8). The idea was to target proteins becoming essential only in the mutated cancer cell. This synthetic lethal approach had been demonstrated in yeast and as a concept sounded very attractive as a treatment of cancer.
Chemotherapeutic drugs trigger Homologous Recombination
Many anti-cancer drugs work by causing DNA damage which becomes lethal at replication forks. However, what happens exactly at the replication fork and what lesions are formed is poorly understood. I thought that if we could have a better understanding how current therapies work this may be a way forward to create new and improved treatments. In my PhD, I found that homologous recombination is triggered to repair the chemotherapeutic drug lesions at replication forks, and hence made the treatments less effective. I was very intrigued in how homologous recombination worked since inhibiting this could potentially provide better treatments.
The birth of the PARP-BRCA story
Being a PhD student I came to know one of the individuals who first demonstrated DNA is frequently damaged and repaired. His name is Tomas Lindahl and he founded and directed the world’s most prestigious DNA repair institute, the Clare Hall Laboratory, outside London. Every time I met him and told him I was working on homologous recombination, he told me that PARP was the key player in homologous recombination. Being both Swedish and named Tomas I had to listen to this intelligent individual. After my PhD Tomas invited me to work in his laboratory studying PARP and recombination in yeast as a model organism. The problem was that Arne Klungland (from Norway) had started on that project in Tomas’ lab 5 years earlier, showing PARP is lethal to yeast. Arne told me that this was “a postdoc killing project”. I declined Tomas’ nice offer and went to work with Prof Mark Meuth in Sheffield, who short thereafter offered me a lectureship and the opportunity to start my own laboratory, to study PARP and recombination in mammalian cells. Prof Herbie Newell (Newcastle) visited us and sent us the potent PARP inhibitor (NU1025) he had developed by improving the first ever PARP inhibitor from Sydney Shall. In the year 2000 my first technician, Elena Lopez, carried out the critical experiment showing that recombination defective cells were sensitive to PARP inhibitors.
At this time, everyone knew from the work of Ralph Scully and others that BRCA1 and BRCA2 bound RAD51 and were likely involved in homologous recombination. It was a race we all participated in to show these proteins were involved in homologous recombination, and a race won by Maria Jasin who had developed a new and clever way of studying recombination by GFP activation in cells. In 2002, we received BRCA2 defective cells from the late Małgorzata Zdzienicka, so that Dan Flower could test their PARP inhibitor sensitivity. I still remember the sunny day in 2002 Dan came to my office, uninterested and in despair saying “The experiment didn’t work, all the cells died”. I told him the control cells didn’t die and he had to go back and dilute the PARP inhibitor more. Gloomily, he did and found a dose response in BRCA2 defective cells at a 1000-fold lower concentration than killed normal cells. Seeing this, it was clear to me this would be a paradigm shift. I told him “Dan, this is a historic day that will change the way we treat cancer”. From Dan’s look (dimmed by his nightly DJ activities) I could see his was thinking “This is one of Thomas’ crazy days”. Round about that time, a highly motivated postdoc from London, Helen Bryant, joined my small team and together in a fantastic collaboration with Nicola Curtin in Newcastle, we could finalise the story that years later was published in Nature.
What we demonstrated was a synthetic lethal relationship between PARP-BRCA that had a therapeutic value. PARP Inhibitors can kill the BRCA mutated tumours without being toxic to normal cells. Since then, many examples of synthetic lethality are demonstrated, but unfortunately very few have been progressed into the clinic.
The Helleday Laboratory in Sheffield 2003.
From left to right Songmin Ying, Nasrollah Saleh-Gohari, Dan Flower, Kayan Parker, Jaroslaw Dziegielewski, Helen Bryant, Ponnari Gottipati, Anu Kumar and Thomas Helleday.
PARP inhibitors towards the clinic
Steve Jackson in Cambridge realised early on the potential of targeting the DNA repair and damage response pathway for treatment of cancer. This was certainly not obvious at the time and he managed to get an extraordinary group of excellent scientists together to start the company KuDOS, who rapidly developed inhibitors to ATM, DNA-PK, MGMT and PARP. In Sheffield, we eventually managed to convince the technology transfer office that we were onto something new worth patenting (filed July 2003), which later was licensed to KuDOS who were developing PARP inhibitors and took these into patients.
One particular BRCA mutated patient ‘Marie’ contacted me and asked for a PARP inhibitor. I sent her to Lund, where Niklas Loman was running a PARP trial. Half a year later Marie replied to me and told me her ca125 marker dropped to normal levels and that the tumour no longer could be measured. This was extremely encouraging and at the time, we thought the path to a FDA approval would be an easy ride, given olaparib was an excellent PARP inhibitor without severe side effects and BRCA patients were easy to identify. We couldn’t be more wrong and the big lession learnt is that when embarking on a novel way of treating cancer a novel strategy in clinical trials is also required, especially where biomarkers are not obvious. For myself, the full bench-to-bedside path from a basic science discovery to responding patients was very interesting and motivating and is a path that has influenced our laboratory in everything we do. Now we hope many, like Marie, can benefit from PARP inhibitors.