PARP Inhibitors- A Breakthrough in Breast Cancer Treatment
Apr 15, 2005, 18:18, Reviewed by: Dr.
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Now, scientists � funded by Breakthrough Breast Cancer and Cancer Research UK � at the Breakthrough Toby Robins Breast Cancer Research Centre (London) in collaboration with KuDOS Pharmaceuticals (Cambridge), report that a new drug, known as a PARP* inhibitor, may be very effective in killing tumour cells in people who have faults in BRCA1 and BRCA2. The drug is likely to be much less toxic to healthy cells than standard chemotherapy.
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By KuDOS Pharmaceuticals, Cambridge, Uk,
According to new research published in Nature today (14 April 2005), UK scientists have identified a potential new drug which could dramatically improve the treatment of patients with certain types of hereditary breast cancer and herald a new approach to targeted cancer therapy.
Women carrying faults in the BRCA1 and 2 genes have up to an 85% chance of developing breast cancer by the age of 70. Currently there is no specific treatment available for these women.
Now, scientists � funded by Breakthrough Breast Cancer and Cancer Research UK � at the Breakthrough Toby Robins Breast Cancer Research Centre (London) in collaboration with KuDOS Pharmaceuticals (Cambridge), report that a new drug, known as a PARP* inhibitor, may be very effective in killing tumour cells in people who have faults in BRCA1 and BRCA2. The drug is likely to be much less toxic to healthy cells than standard chemotherapy.
Professor Alan Ashworth, Director of the Breakthrough Research Centre � situated at The Institute of Cancer Research � who led the research in London, said: �This is a brand new therapeutic approach, centred on exploiting a specific deficiency in breast cancer cells � their Achilles� heel. This is only possible because of our ever-increasing understanding of the basic molecular biology of cancer.� Professor Ashworth was instrumental in the discovery of the BRCA2 gene in 1995.
In the UK, nearly 41,000 women are diagnosed with breast cancer each year. Of these, 5% are due to strong hereditary factors, some of which are caused by BRCA1 and BRCA2 mutations.
Most breast cancer patients are treated with drugs that kill tumour cells but also damage normal cells. It is damage to normal cells that can lead to distressing side effects, like nausea and hair loss. The advantage of this new approach is that it is targeted; tumour cells are killed while normal cells appear unaffected. This is because the new class of drugs, PARP inhibitors � being developed by KuDOS Pharmaceuticals � exploit the specific genetic make-up of some tumour cells.
Breast tumours in women who inherit faults in either the BRCA1 or BRCA2 genes occur because the tumour cells have lost a specific mechanism that repairs damaged DNA**. PARP inhibitors selectively kill cells where this form of DNA repair is absent and so are highly effective in killing BRCA deficient tumour cells and other similar tumour cells. Normal cells are largely unaffected by the drug as they still possess this crucial DNA repair mechanism.
Dr Andrew Tutt, a Clinician Scientist at the Breakthrough Research Centre and Breast Oncologist at Guy�s Hospital, said: �Targeted treatment holds considerable clinical promise. If our laboratory findings are confirmed in the clinic, we could dramatically improve the treatment of patients with BRCA1 or BRCA2 associated cancers. This is a completely new approach in our fight against this type of cancer.�
KuDOS, a leading privately owned oncology company, has been developing the PARP inhibitor programme since 2000. Professor Steve Jackson, Chief Scientific Officer of KuDOS, who founded KuDOS in1997, commented: "This is the first time that a PARP inhibitor has shown significant promise as a treatment for breast cancer. This discovery could well be the tip of the iceberg, as the DNA repair technology behind this programme has the potential to treat a range of other cancers that display similar characteristics."
Dr Lesley Walker, Director of Cancer Information at Cancer Research UK, said: "Collaborations like this, that bring together all the necessary expertise, are crucial for the rapid and effective translation of fundamental research into a new generation of smart cancer treatments."
The PARP inhibitors will enter Phase I trials within a few months, to monitor the safety of the drug and determine the most effective dose to take into larger clinical trials. If these trials are successful, these drugs will be ready for testing in clinical trials of patients with BRCA deficient tumours.
This new treatment might also be applicable to other forms of breast cancer that behave like BRCA deficient cancer. This group may represent more than 20% of all breast cancers and is a key area of research in Professor Ashworth�s laboratory. 
- Targeting Specific DNA Repair Pathways as a Therapeutic Strategy for Tumours Defective in BRCA1 or BRCA2. H. Farmer, N. McCabe, C.J. Lord, A.N.J. Tutt, D.A. Johnson, T.B. Richardson, M. Santarosa, K.J. Dillon, I. Hickson, N.M.B. Martin, S.P. Jackson, G.C.M. Smith and A. Ashworth. (2005) Nature.
www.kudospharma.co.uk
This project, in collaboration with Kudos, is just one example of the ground-breaking research taking place at the Breakthrough Toby Robins Breast Cancer Research Centre. This year the centre, the UK�s first facility dedicated to breast cancer research, celebrates its fifth year of pioneering research, based in the Mary-Jean Mitchell Green Building at The Institute of Cancer Research.
This work was funded by Breakthrough Breast Cancer, Cancer Research UK, The Wellcome Trust and the Mary-Jean Mitchell Green Foundation.
* PARP stands for poly (ADP-ribose) polymerase.
** Termed homologous recombination.
� Breakthrough Breast Cancer is a charity committed to fighting breast cancer through research and education. More information can be found at our website www.breakthrough.org.uk or through the Breakthrough Information Line 08080 100 200.
� Breakthrough needs to raise at least �10 million a year to fund our pioneering research and education work.
� The Breakthrough Toby Robins Breast Cancer Research Centre is the UK�s first facility dedicated to breast cancer research into prevention and treatment, based in the Mary-Jean Mitchell Green Building at The Institute of Cancer Research. The centre is currently made up of seven teams focusing on: Gene Function (understanding more about the genes which cause breast cancer); Molecular and Cellular Biology (why some tumours spread while others don�t); Pathology (looking at normal breast tissues and seeing how they differ from breast cancer tissues); Novel Drug Targeting Team (finding new drugs which specifically target breast cancer genes, causing fewer side effects); Apoptosis (finding out why cancer cells do not die but keep multiplying); Molecular Radiation Oncology (looking at the genes which can help deal with cancer-causing substances); and Molecular Endocrinology (looking at breast cancers that are hormone dependent).
� KuDOS Pharmaceuticals Limited, a spin out company from Cancer Research UK, holds a leading position in the discovery and development of small molecule drugs based upon the science of DNA damage sensing, signalling and repair to address unmet medical needs in cancer treatment. KuDOS currently has two drugs in clinical trials: Patrin�, which is being developed for the treatment of cancers resistant to alkylating agents, and banoxantrone (AQ4N), which targets hypoxic regions of tumours. Research continues on DNA-PK, ATM, PARP and mTOR inhibitors, with a candidate compound for PARP currently in preclinical assessment. For more information about KuDOS please visit, www.kudospharma.co.uk.
� Breast cancer is now the commonest cancer in UK women, accounting for nearly 1 in 3 of all female cancers.
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