Overview
In 2005, Professor Alan Ashworth, Dr Andrew Tutt and colleagues at the Breakthrough Research Centre published their work showing that cells with faulty BRCA genes are highly sensitive to PARP-inhibitors. A preliminary Phase I trial in 2006/07 was highly successful, and two Phase II trials are now underway investigating PARP-inhibitors for women with breast or ovarian cancer linked to inheriting a faulty BRCA gene.
The BRCA1 and BRCA2 genes are important for the repair of DNA double-strand breaks by homologous recombination. When the function of these genes is lost, cells are unable to repair damage to their DNA and this predisposes the individual to breast and other cancers.
Poly(ADP-ribose) polymerase (PARP) is a key enzyme involved in the repair of single-strand breaks in DNA via the Base Excision Repair pathway. Breakthrough scientists found that cells deficient for either BRCA1 or BRCA2 are particularly sensitive to the inhibition of PARP enzymatic activity; this results in chromosomal instability, cell cycle arrest and subsequent apoptosis.
Research Aims
The two Phase II clinical trials are being conducted by Kudos pharmaceuticals, a subsidiary of AstraZeneca. The aim of the trials is to evaluate the effectiveness of AZD2281 (KU-0059436), a PARP inhibitor, in patients with an inherited mutation in one of the breast cancer susceptibility genes, BRCA1 or BRCA2.
Dr Andrew Tutt is the Lead Investigator for the trials. Having previously worked at the Breakthrough Research Centre, he is now Head of the new Breakthrough Research Unit at King’s College London, an oncologist at Guy’s and St Thomas’ and an Honorary Senior Lecturer in Research Oncology at King’s College London.
The research team will follow the patients involved extremely closely, looking for indications that the treatment is working, such as tumour shrinkage and also monitoring any side-effects.
These studies are part of the ICEBERG (International Collaborative Expertise for BRCA Education and Research through Genetics) studies, intended to evaluate the effectiveness of PARP inhibitors for cancer treatment.
Contact
Dr Andrew Tutt,
Breakthrough Breast Cancer Research Unit
King’s College London School of Medicine
Guy’s Hospital
London SE1 9RT
E-mail: sora.vorapon@kcl.ac.uk
