Q&A With Dr. Alan Ashworth

BCRF sat down with Dr. Alan Ashworth to discuss his current work and interest in breast cancer research. Read on to learn more.

Q: Tell us about yourself as a scientist and how you became interested in breast cancer research.

A: I thought about a career in medicine, but after studying chemistry, I became very, very interested in understanding basic mechanisms of biology. I became a research scientist and got my own lab when I was very young, at age 27. I was so naïve; I didn’t think there was anything particularly unusual about it!

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.

Q: 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?

A: All cell types sustain DNA damage in their lifespan and need to fix it in order to keep dividing and keep the cell type going. Cancer cells are no different. As with most cells, there are multiple pathways the cancer relies upon for this repair. PARP is one of these pathways.

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.

Q: What makes the BRCA1 and BRCA2 cells different?

A: BRCA1 and BRCA2 have a mutation that turns them into cancer cells. But because of this difference, they also have one DNA repair pathway that is compromised. Treating the tumor with a PARP Inhibitor blocks the BRCA cells’ secondary DNA repair pathway. This second level of failure is more than the BRCA cells can handle, and provokes cell death. This is a win for breast cancer treatment because it shrinks the tumor dramatically. PARP Inhibitors take advantage of the tumor’s known liability.

Q: Will PARP Inhibitors work in other kinds of breast cancer?

A: Yes, they should and we’ve seen evidence suggesting this is the case. In other breast cancers, there are likely faulty DNA repair mechanisms that PARP Inhibitors will exploit. We just happen to know that this is the case with BRCA1 and BRCA2 cancers.

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.

Q: Do PARP Inhibitors have any side effects?

A: So far, they are relatively non-toxic compared to chemotherapy. It is too soon to know the long-term effects, if there are any. The patients in Phase I clinical trials–with us, and with other groups–are essentially incurable. PARP Inhibitors are helping these patients extend their survival. Right now we are looking at PARP Inhibitors in a relatively small fraction of breast cancer patients, and possibly a larger fraction of ovarian cancer. Our priority is to figure out how to use this new drug successfully in a larger group of patients, and earlier in the disease to achieve a cure.

Q: How will you accomplish this?

A: This is where BCRF is indispensable. Whenever there is a new drug that is effective and safe, even in part of a cancer population, it quickly becomes a standard and some opportunities to refine its use are slowed or lost. PARP Inhibitors are so dramatic in what they do that they should be used to aid as many breast and other cancers as possible. Part of this will rest on figuring out which sensitizing drugs to pair them with. We are already conducting quite a few obvious and important clinical trials with PARP Inhibitors, but want to design the next wave of clinical trials based on real data about which drugs and what dosages will be the most reliable with PARP Inhibitors.

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.

Q: Are PARP Inhibitors going to cure breast cancer?

A: We don’t know, but with this kind of discovery, I think we’re getting closer. You see, we already have the means to generate all the answers we need. Think of the mapping power of the human genome project applied to thousands of tumors, giving us all the genetic information for hundreds of different kinds of cancer. This is where we’re going. If we can manage the huge amount of data that we are generating for ourselves, we’ll continue to make significant progress. But this is no small task.

Q: What’s stopping us from just getting all the work done?

A: If you take an average tumor, be it breast or colon cancer, there are about 20,000 genetic changes in that tumor’s DNA compared to normal DNA. Much of those changes is noise; perhaps in all 20,000, only 20 or 50 are functionally needed for the tumor. This is the challenge. We need better ways of identifying these “mission-critical” changes, so that we can focus our attention where it will be the most effective.

Q: What advice would you give to young researchers?

A: First take on an important problem. Then, if you are interested in a disease like breast cancer try to understand the biology of the whole disease as well as focusing on a small aspect. Finally, think very hard about data analysis. Now, in science, there are a lot fewer people doing the experiments and a lot more people analyzing data because there are great tools for generating data, and so much of it. As a researcher in biology today, you absolutely have to have a very strong grounding in mathematical methods in order to concentrate on choosing the clever experiments and the clever ways to manage and interpret data.

Q: Did you ever seriously consider another kind of career than that of the sciences?

A: No, since I started studying the basics of how molecules work and applying it to treating disease, I have never thought of doing anything else. I love my job!

Read more about Dr. Ashworth’s current research project funded by BCRF.