Kornelia Polyak, MD, PhD
Professor of Medicine
Dana-Farber Cancer Institute
Harvard Medical School
Q: Tell us about yourself as a scientist and how you became interested in breast cancer research. Did you ever seriously consider another kind of career than that of the sciences?
A: I have always loved science. As a child in Hungary, I always wanted to do experiments, so from very early on I was hooked on science and medicine. I was fortunate to have wonderful teachers who encouraged this, and by high school I pretty much knew I wanted to do cancer research. I was really good in math and science but I wanted to do something applied and I was also I really wanted to be a doctor. But when I went to medical school, I felt frustrated with many things-sometimes you cannot help people because you don't have enough knowledge or you don't have good medicines that can cure your patients. That's why I decided that I wanted to do medical research: to find better ways to treat people. I feel like I could help more people this way. And I decided to focus on breast cancer in particular after completing my post-doctoral training at Johns Hopkins.
Q: Briefly describe your BCRF-funded research project. What are some laboratory and/or clinical experiences that inspired your work? What are your primary goals for this research?
A: Our BCRF-funded research focuses on understanding heterogeneity (in other words, differences) in breast cancer, specifically heterogeneity within a tumor. We know a tumor is not composed of one type of cancer cell with the same features but of many different types of cells. And the problem is that the more different types of cancer cells there are within a tumor, the more likely this cancer will progress and be able to resist treatments. Current drugs are capable of targeting only some types of cancer cells at a time, but not yet multiple ones.
We are studying tumor heterogeneity in patient samples collected during the course of these individuals' treatments. We are trying to understand how tumors "evolve" in response to treatment and how we may be able to predict which cancer cells will be the resistant ones, so that we can design better treatment strategies based on this knowledge. For example, if you apply a tumor with drug A, the cancer cells that are resistant to the drug will survive and continue to grow. So, the tumor evolves. If at the time of diagnosis, we know all the types of cancer cells that are within a tumor and can predict which cells may not respond to treatment, we could potentially prevent therapy resistance by prescribing a different or an additional drug. Evolution in the tumor also includes turning from localized disease to metastatic disease.
At the same time, we are also experimenting with breast cancer models to try to understand the functional relevance of heterogeneity. Why is there a particular combination of cancer cells in a tumor? Is it because cancer cells talk to each other and particular combinations of cells prefer to grow together, and so on? We are also trying to understand why that is and how we could again exploit this knowledge to better treat cancers. Maybe if we understand the communication among the cancer cells within a tumor, then we can interrupt this communication in addition to killing the particularly bad type of cancer cells. So that is our goal-- basically to develop better ways to predict the evolution of the tumor and also to prevent this evolution, particularly treatment resistance and metastatic progression.
Q: Are there specific scientific developments and/or technologies that have made your work possible? What additional advances can help to enhance your progress?
A: Improvements in technologies that have advanced tremendously over the past two years are now allowing us to assess many characteristics of the tumor, even in individual cancer cells in situ. The older technologies allow us to look sections of cells. We would grind up a tumor, let's say even a small tumor of 1 cm size, and we would be able to get only the average of what is in the tumor. The technologies now allow us to sequence the whole genome of a single cancer cell or determine the genes expressed in a particular cell. That certainly seems extremely useful because we can get really in-depth understanding of the tumor's composition. So, instead of just looking at the average, we now are looking at what are those individual cancer cells that give rise to the tumor. These single cell studies could enhance our understanding of heterogeneity.
Another thing we do is integrating different types of science in our work. For example, we conduct molecular studies but we collaborate with mathematicians and even physicists on looking at the evolution of the tumor. We use mathematical models to predict the evolution and use the same kind of equations used in ecology to look at evolution of an ecosystem. We integrate these disciplines to help us better understand cancers.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: On the positive side, more and more, we are trying to individualize therapy for everyone. I have a somewhat science fiction point of view, which hopefully will not be science fiction much longer. What I picture is this: when a patient is diagnosed with cancer, we would be able to assess her tumor in-depth, at the single cell level. Then, we could put the tumor's characteristics into a computer. Next, based on the computational models we have built and are building, we would be able to simulate what happens to the tumor using various treatment options. These simulations would help us determine the best option for this particular patient. It may sound like science fiction, but there are already computer programs that do this in a much less sophisticated way, and I think if we develop this potential, then individualizing therapy will advance even more. As we know more about the behaviors of the tumors and the probable behaviors of the tumors in response to therapies, while simultaneously continue to develop more and more effective treatments, then we can truly individualize and tailor treatment for patients. I think this will be happening more and more in the next five to ten years.
An issue that worries me and others in the science community is the future of research. We need to make sure that we do not lose the next generation of researchers. The situation with significantly reduced federal funding is scaring many young trainees from an academic research career. Even our lab, arguably one of the best in breast cancer research, has received rejections in the last two years from the National Institutes of Health (NIH) because it has reduced funding to only 5% of the research projects submitted for review. This trend is not sustainable. Most labs cannot survive this lack of funding. If young trainees are seeing that even the more senior, established labs have difficulties getting funding, then they question how could they even go into this field.
Also, training for a scientific research career takes 10 to 15 years. So if you are discouraging college and graduate students from staying in academic medicine, you cannot quickly reverse this loss of human capital. This "brain drain" is not going to be good for academic research or for the country in general.
The lack of funding is also pushing many agencies now to plan very formulaic research, or "safer" projects, that appeals to conventional funding mechanisms. This trend is worrisome because "playing safe" may impede, rather than enhance, progress. This situation is happening not only in laboratory science but also in clinical research. There is a huge demand for physician-scientists, and there needs to be additional support mechanisms to ensure that the young, best and brightest, and most enthusiastic people do not get discouraged. This is a situation that is unfortunately not getting enough attention.
Q: What other projects are you currently working on?
A: Our lab is working on two other major areas. One is to understand why women get breast cancer and how we can prevent it. While I want to treat breast cancer, ideally I would prefer to prevent it. To do this, we are studying the normal breast tissue of women who have high risk of breast cancer, for example BRCA1 and BRCA2 mutation carriers or women who have not had children. We are trying to understand the difference between the normal breast tissues of someone at low risk of breast cancer versus that of someone at high risk and how we could change this risk. We are very excited about what we have found in our studies so far. It appears that some cell types seem to be more frequent in women at higher risk of breast cancer, and these cells divide and act kind of like progenitor cells (or stem cells) in the breast. The reason why we are excited about these findings is because we also have ways to eliminate these cells. So theoretically, if you could eliminate these cells, then you could also reduce the risk of breast cancer and maybe even prevent it.
Another area our lab focuses on is epigenetics, in particular focusing on triple negative disease. Many tumors have very few genetic changes. The recent whole genome sequencing of tumors showed that particularly in some bad types of breast cancer, like triple negative disease, there are not too many mutations that we could target with therapies. Epigenetics is looking not just at the genetic alterations in the tumors but also other changes. Epigenetic regulations are basically what determines the function of a cell and whether it becomes a differentiated cell or not, and these regulations frequently to go wrong in cancer. Cancer cells seem to lose their "identity" in a way and become whatever they want. We are trying to understand what is supposed to go on in a cell during its normal development and then what are the abnormalities, such as particular proteins breaking or not doing their specific function, which take place instead and turn normal cells into cancer. We are also trying to see if these epigenetic changes can be targeted through drugs.
Q: How close are we to preventing and curing all forms of breast cancer?
A: We are very excited about the project on normal breast tissue in high risk women, because if we are correct about these cells-of-origin of breast cancer and if we have ways to eliminate these cells, then we could potentially prevent breast cancer. And this prevention would not involve continuous and highly toxic treatments, but possibly doing a type of treatment that mimics pregnancy. We are doing additional studies along these lines on larger cohorts of women. While prevention studies are always difficult to prove, I am optimistic that an approach like this could be done in the next decade or so.
In terms of cure, I do not know if we can ever cure all forms of breast cancer. However, I do think that many cases of breast cancer are curable now. I am optimistic that with the new knowledge we have and will continue to accumulate on heterogeneity and epigenetic targets, we will have major advances in five to ten years, even for the hard-to-treat types of breast cancer, such as triple negative disease and inflammatory breast cancer. I tend to be optimistic and I really want to believe that we will have major advances soon.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: BCRF has been a major supporter of many researchers who focus on breast cancer and has been really helping the field tremendously. BCRF funding enables us to take on risky projects for which it would be very difficult to obtain conventional government grants, especially now. And BCRF allows us to test ideas, really exciting new ideas. I think it is kind of ironic that while the goal of research should always be to test new ideas, it is difficult to find funding sources for this.
BCRF has been really great, also because it supports individuals who have a proven track record of solving problems in research and are committed to breast cancer, instead of very specific projects. I think this is the way that research in general should be funded, but it is not. I know everybody who is part of the BCRF family is truly thankful to be part of it.