Tuesday, 27 November 2012

"PARPhylactics": is prophylactic use of PARP inhibitors possible

Prof Steve Jackson presented a great seminar today at CRI on his labs work on DNA damage repair. One of the numbers that jumped out at me was 1,000,000, that is 1M DNA damage events per cell per day.

Just think, even with all that going on it still takes most of us 60 years to get cancer!
63% of cancers are diagnosed in people aged 65 or older.
 

Prof Jackson was also one of the founders of KuDOS Pharmaceuticals Ltd. This venture was acquired by Astra Zeneca in 2005 and resulted in the PARP inhibitor Olaparib. Steve gave us a wonderful journey through the incredibly complex world of DNA repair and it's array of protein complexes and regulatory networks. He finished by by talking about teh therapeutic opportunities and how PARP inhibitors can be used to induce a chemo-biologic "synthetic lethality in Cancer cells, whilst being relatively innocuous to normal cells. One of the things I learned is that KuDOS pharmaceuticals took its name from the Ku protein, which binds to DNA double-strand breaks and creates a molecular ladder or scaffold that other proteins involved in NHEJ can bind to. 

PARPhylatics: One of Steve's slides showed a graph of how drug toxicity is affected by dose and genotype. There was a 1250x increase in sensitivity to the PARP inhibitor Olaparib for -/- compared to +/- or +/+ BRCA patients. This kind of sensitivity it did make me wonder if low doses of PARP inhibitors might be a sensible prophylactic treatment for specific groups of patients. 

I asked a question after Steve's presentation, "might PARP inhibitors be used in patients with germline DNA repair mutations to prevent or delay cancer development". Steve's response was that this may be possible but there are lots of unanswered questions about this kind of use in patients.
 

Of course patients with these germline mutations can have very agressive treatment in the form of mastectomy (removal of the breasts) and/or oophorectomy (removal of the ovaries). Both of which can significantly reduce a women’s risk of breast or ovarian cancer. What the additional risks might be of PARPhylactics is going to take some time to work out. I'll certainly be keeping my eye out to see what Steve's new company MISSION Therapeutics Ltd does. There are lots of different players in the DNA damage repair pathways and it sounds like many will turn out to be interesting and druggable targets.

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