Alan Ashworth, BSc, PhD, FRS

2012-2013 BCRF Project:
(made possible by generous support from Hard Rock Café International, Inc.)

With previous funding from BCRF, Dr. Ashworth has investigated whether microRNAs (miRNAs), a subset of RNA molecules, change the way that breast cancer cells respond to PARP inhibitors, a relatively new class of drug. They have assessed whether microRNAs that control PARP inhibitor sensitivity also change the response of tumor cells to other types of cancer therapy, including radiotherapy, which turned out to be the case. Their findings suggest that the specific miRNAs Dr. Ashworth's group identified do in fact change a process known as DNA repair.

In 2012-2013, Dr. Ashworth and colleagues will continue the miRNA project, working on several fronts. First, they will establish precise mode of action of the miRNA, mir-107, to unequivocally demonstrate its mechanism of action. They propose to mutate miRNA binding sites in order to reverse the increased sensitivity to the PARP inhibitor, olaparib. They will also further establish the generality of mir-107's effects. At present, the majority of this group's studies have focused upon two breast tumor subtypes; they will expand to models of other breast tumor subtypes. Dr. Ashworth's team will also perform additional bioinformatic analyses. It seems possible that some of the effects these scientists have identified are the result of a combination of gene silencing effects. Further bioinformatic analysis may enhance their understanding of this process.

In addition, Dr. Ashworth's team will pursue identification of tumor suppressor miRNAs that drive genomic instability and PARP inhibitor sensitivity. Until now, the techniques for suppressing miRNA function have been hampered by the relative limitations of miRNA inhibitor libraries. These investigators have now pioneered a novel method of genetic screening. Their newly developed system allows the rapid identification of loss of function in genes associated with drug sensitivity. Dr. Ashworth proposes to use this system in PARP inhibitor screens to identify miRNA that, when repressed, cause sensitivity.

Mid-year Progress: Since their last report, Dr. Ashworth's team has finalized their work on assessing whether microRNAs control PARP inhibitor sensitivity. They have found that particular miRNAs change PARP inhibitor sensitivity by changing the levels of a key DNA repair protein, RAD51. Furthermore, they have started a new project that uses novel technology, known as HTP screening, to understand better why some patients respond well to PARP inhibitors, while others do not.

Bio:
Professor Alan Ashworth FRS, is Professor of Molecular Biology, Leader of the Gene Function team in The Breakthrough Breast Cancer Research Centre and CEO of the Institute of Cancer Research (ICR).

Alan Ashworth joined the ICR in 1986 as a postdoctoral scientist in the Section of Cell and Molecular Biology and in 1999 he was appointed the first Director of the Breakthrough Breast Cancer Research Centre. The Centre is now recognized internationally as one of the leading breast cancer centers and has more than 120 scientists and researchers working on aspects of the disease, ranging from basic molecular and cellular biology through to translational research and clinical trials. Professor Ashworth's Directorship ended in January 2011 when he took up the position of Chief Executive of the ICR.

One of Professor Ashworth's major contributions has been his work on genes involved in cancer risk. He was a key part of the team that in 1995 discovered the gene BRCA2, which is linked to an increased risk of breast and ovarian cancers. Ten years later, Professor Ashworth identified a way to exploit genetic weaknesses in cancer cells including mutated BRCA2, leading to a new approach to cancer treatment.

His current research reflects his passion for the development of personalized cancer medicine, translating laboratory studies into improvements in patient care. He is also joint leader, with Professor Tony Swerdlow, of one of the world�s most comprehensive and largest (>100,000 participants), studies of breast cancer causation, the Breakthrough Generations Study (http://www.breakthroughgenerations.org.uk).

Professor Ashworth is an elected member of European Molecular Biology Organization (EMBO) and the Academy of Medical Sciences. His contributions to mammalian genetics and identification and study of inherited breast cancer susceptibility genes saw him elected as a Fellow of the Royal Society in 2008. He has been the recipient of a number of scientific prizes and awards including The European Society of Medical Oncology Lifetime Achievement Award, the David T. Workman Memorial Award of the Samuel Waxman Cancer Research Foundation and the Meyenburg Foundation's Cancer Research Award.