Q&A with Alan Ashworth, BSc, PhD, FRS
Professor, Molecular Biology and Director, The Breakthrough Breast Cancer Research Centre
BCRF: Tell us about yourself as a scientist and how you became interested in breast cancer research.
I wasn't focused on breast cancer until a friend of mine in the U.K., Mike Stratton, asked if I could help him with a project. Basically, he needed more hands on a search for a high-risk gene in breast cancer. This was in late 1994.At that point, BRCA-1 had already been discovered, and together we found BRCA-2 by the end of that year. Things were happening so fast, we found the gene and it was published three weeks later! This was thrilling, but what happened next was even more of a revelation: within days of discovery of the gene, a woman was tested for it at Royal Marsden hospital in London. She had already been scheduled for a prophylactic mastectomy because of breast cancer in her family, but because she could be tested which revealed that she didn't have the gene, she didn't have the surgery. New knowledge steered her and her doctor in decision-making. I then became much more interested in applying basic biology to breast cancer research.
BCRF: You are known for your important discovery that drugs called PARP inhibitors could be used to treat BRCA-1 and BRCA-2 related cancers. How did this come about?
Not long after our discovery, I had one of those coincidental encounters that change your life: I met someone who wanted to talk to me about some drugs—and by that I mean drugs that his company was developing! They were PARP Inhibitors from a company called Kudos, which is now part of AstraZeneca. Since our lab studies the BRCA-1 and BRCA-2 breast cancer cells, we put the experimental drug on them. What we found was astonishing. The BRCA cells were one thousand times more vulnerable to these drugs than normal cells! They couldn't survive. Their high sensitivity means that the drug could be very effective. The BRCA cells have a different liability than normal cells and PARP Inhibitors target that liability.
BCRF: What makes the BRCA-1 and BRCA-2 cells different?
BCRF: Will PARP Inhibitors work in other kinds of breast cancer?
There are also ways to provoke faulty DNA repair and other kinds of challenges in tumor cells. This is what happens with chemotherapy, and we are studying whether or not adding PARP Inhibitors to chemotherapy will exponentially kill cancer cells. Early results are promising.
PARP Inhibitors may change the entire landscape of cancer treatment. For example, 80 percent of uterine cancers, 25 percent of colon cancers and 25 percent of melanomas have mutations to a gene called PTEN that causes DNA repair damage. PARP Inhibitors should be effective wherever there is compromised DNA repair.
PARP Inhibitors will likely be relevant to up to 50 percent of ovarian cancers. Ovarian cancers are known to be sensitive to platinum drugs. Platinum, a metal found in existing therapies like cisplatin and carboplatin, works like a "dirty" PARP Inhibitor. So, PARP Inhibitors may do the same job, only better.
BCRF: Do PARP Inhibitors have any side effects?
BCRF: How will you accomplish this?
To this end, we are conducting a massive screening of all possible combinations of drugs with PARP Inhibitors. We are looking at thousands of drugs and many more thousands of combinations. It would take many years of human labor to get this data, but with a robotic system that we are using, we hope to get it within months. Without BCRF funding, this step would not be possible. BCRF has given us the ability to fast track something really important.
BCRF: Are PARP Inhibitors going to cure breast cancer?
BCRF: What's stopping us from just getting all the work done?