Donald McDonnell, Ph.D., is an influential translational scientist, mentor and educator whose research has focused on better understanding estrogen receptor signaling in breast cancer. Approximately 70 to 75 percent of patients are diagnosed with estrogen receptor positive (ER+) breast cancer, and his learnings are critical for developing additional treatment options and furthering our understanding of breast cancer recurrence and metastasis. His work has led to the development of a new class of drugs that are now in clinical trials for endocrine therapy-resistant, ER+ metastatic breast cancer.
He tells Susan G. Komen that the last 30+ years of research in breast cancer treatment has produced advances that will change the way we treat aggressive and treatment-resistant breast cancer.
McDonnell, who is the Glaxo‐Wellcome Professor of Molecular Cancer Biology, Department of Pharmacology and Cancer Biology, Professor of Medicine, Co‐Director, Women’s Cancer Program, Duke Cancer Institute, Duke University School of Medicine, is this year’s recipient of the 2020 Susan G. Komen Brinker Award for Scientific Distinction in Basic Science. He is being recognized with Komen’s highest honor for the advancements he’s made in breast cancer research and medicine. He recently spoke with Susan G. Komen about his research.
Komen: What is the focus of your current research?
McDonnell: I decided when I was a young investigator to come at breast cancer from a very mechanistic point of view, to understand what pathways in the cell that drive cancer and how best to interfere with them. And I was very specifically interested in estrogen receptor positive breast cancers. The plan was to figure out how the estrogen receptor worked in breast cancers, how best to inhibit it, how to use this information to develop new classes of drugs that modulate the estrogen receptor that could be used not only to treat patients with early stage disease, but also for patients with metastatic disease. So, for most of my career, my colleagues and I have been trying to develop the better mouse trap, if you want.
But in the last two to three years, we’ve taken a different tack, completely and absolutely turned our whole program on its head. We were all focused on the cancer cell and trying to hit the estrogen receptor within the cancer cell…harder and harder. But we were ignoring the fact that nearly every other cell in the tumor also contains the estrogen receptor, and most of these are immune cells. This work originally funded by Komen, led to another very large grant to address this question. Although we’re still in the midst of our research, the results are telling us what the next generation of estrogen receptor modulators should look like. They are probably not going to look like the drugs we have right now, because most of the current treatments actually have less than desirable effects on the immune system.
Komen: When we think about eventual cures for breast cancer, some doctors and researchers think the immune system can be taught to recognize and kill cancer cells. Do you share this same belief?
McDonnell: If you ask most people who are interested in tumor immunobiology, they’ll tell you that, well, there’s a very good reason lung cancer, and melanoma, and colorectal cancer are the cancers that respond the best to immunotherapy. The reason is because those cancers are highly mutated, having altered proteins that are detected by the immune system. A lot of people will also tell you that breast cancer probably won’t respond to immunotherapy, because it’s what’s called “immunologically cold.” But I’m not really one who subscribes to that thinking. I think rather than throwing in the towel, I actually want to do more to understand, well, why is it a cold tumor and what can we do to make it a hot tumor? So, one half of the field says, well, boy, that’s it. It’s not going to work there. But my argument is, well, let’s find another way. And I will say that right now, it looks very good. Indeed, we recently published a paper describing a Komen-funded study that highlighted a new approach to increase the immunogenicity of breast tumors.
This is probably the most exciting research I’ve ever worked on in my life, and a lot of the insights we’ve got from this work are actually helping us in other cancers. We have clinical trials starting, not in breast cancer, but in melanoma, colorectal cancer and gastric cancers, where we will evaluate the ability of specific estrogen receptor modulators to appropriately modulate the immune system. The only reason we haven’t got to breast cancer yet (clinically) is because as luck would have it, breast cancer seems to be the most complex of all the diseases we have studied!
Komen: How is your research helping us to better understand and treat metastatic disease?
McDonnell: The primary goal of my research is to develop drugs/approaches to treat metastatic disease. Obviously, we’d like to get rid of (prevent) primary tumors, as well, but for the 42,000 women (and men) who die every year from breast cancer in the U.S., its metastatic disease that is fatal. We know the biology of a primary tumor is not the same as the biology of a metastatic tumor, and so it stands to reason that how we treat them might not be the same. So now, where possible, we are trying to develop/use models that more appropriately read on the disease we are trying to treat.
I have been involved in drug discovery for my entire life, and we have made a tremendous amount of progress in the past 40 years, and this has laid the foundation for our current advances. In my own work experience, by understanding the biology of the estrogen receptor, we were able develop an entirely new subclass of drugs, known as oral selective estrogen receptor downregulators (SERDs) that target the estrogen receptor in a new way. Currently, there are 12 SERDs in development for use in patients who have progressed on first line endocrine therapies, and all were developed using mechanism-based discovery approaches that leveraged findings that came from fundamental basic research in estrogen action. Informed by a better understanding of estrogen receptor action in cancer cells and in other cells in the tumor, we are now working on the development of the next generation of ER-modulators and continue to explore how best to pair ER-modulators with drugs that hit other targets in breast cancers. In my opinion, this field of endocrine therapy is far from “mature,” as some believe, and that the best is yet to come.
Further, I believe that when we can appropriately engage the immune system, we can shift the conversation from treating metastatic cancer to curing it. One of the major advances we have seen in our field is the shift to treating breast cancer as a chronic disease. Now it is time to push harder and move to the next level. We’re starting to be able to use the word ‘cure’ in HER2 positive breast cancers. I’d like to be able to use that in estrogen receptor positive cancers as well.
Komen: What drew you to the field of breast cancer?
McDonnell: When I was 17 years of age, I went to a local dance and met Mary, who is now my wife and best friend. But the reason Mary was there with her sisters that night was because her mother (Agnes) had been diagnosed with breast cancer that day, and her father needed to sit down and have a chat with her mother. Three years later while in my second year at college, Mary’s mother’s disease had recurred and metastasized. Mary used to call me once a week (no cell phones, texts or email those days!) and would ask me questions about breast cancer and/or to help her get information about her mother’s disease. I’d go to the library look up the papers or ask some of the medical students I played rugby with to get me information. About six months into this, I said, “I’m really enjoying this much more than the courses I’m taking, and I could see a future in this.”
But I had a problem, I had a four-year scholarship from an environmental organization (Limerick Harbor Commission) to study marine biology. So, I went to the director of the organization (Mr. Michael Hoctor) and I said, “I’ve got a problem here. I love marine biology. It’s what you’re sponsoring me for. But my passion has changed.” And I told him the story about Mary’s mother and how my interests had changed. Mr. Hoctor, without a blink of an eye said, “Keep your scholarship, change your courses, and hopefully you will do something that will help my wife or my daughters if they get breast cancer.” So, I did, and I graduated with a degree of biochemistry from the University of Ireland (Galway).
As luck would have it my undergraduate advisor, Dr. Denis Headon, was doing a sabbatical in the laboratory of Dr. Bert O’Malley at Baylor College of Medicine (Houston) and he used to write to me and call me every once in a while to tell me about the work that this lab was doing in hormone action. One thing led to another and next thing I know it I am a graduate student in Houston studying with Dr. O’Malley. Definitely needed the “luck of the Irish” for all these things to happen and it is ironic that I would never actually have met my wife if it wasn’t for her mother’s breast cancer.
Komen: Unfortunately, breast cancer is a personal disease for so many. The statistics are 1 in 8 women in the U.S. will get it, but the one might be your mother, or daughter or neighbor.
McDonnell: It is. One of things that is very important to me and I’ve tried to do the same thing with my trainees, is to encourage them to participate in Komen’s patient-focused events, and to go there and to listen to the stories of how breast cancer has impacted these women (and men) and their families. I do that because research is really hard. It’s disheartening. I think that if you’re not used to failure, go find something else to do, because 90 percent of what we do just doesn’t work. So, I think that especially with graduate students where they’re young and impressionable, it’s very useful for them to meet with patients, or the medical oncologists. And we do that, I do that all the time, because I think you have to put a face with the disease to be able to impress upon people how important their research is.
Komen: What do you think is possible in the next 10 years for breast cancer research?
McDonnell: We’re making very significant inroads into personalized medicine, understanding what the drivers are in late stage and earlier stage diseases. We’re now having success targeting those drivers that were never targetable before, not receptors, or enzymes, but other tough nuts in the cell that have been difficult to crack. We are also learning how best to harness the immune system to target breast cancer with some success already noted in triple negative beast cancer (TNBC). This is going to be “big” and it’s going to put us in a better position to unleash the immune system. Even if we get the fantastic drugs that kill 99.99 percent of cancer cells, I think we still need to unleash the immune system to be able to get completely eradicate residual disease from the body. I really do believe that in my lifetime, as a scientist, we will be much more comfortable using the word cure.