Emerging Areas of Treatment with Dr. Donald McDonnell

This week on Real Pink we are hosting daily conversations about breast cancer that hides in the shadows: metastatic breast cancer (MBC).

In the US alone, MBC is expected to kill 42,000 people. This special episode, featuring Dr. Donald McDonnell, is part of National Breast Cancer Awareness Month.

About Dr. McDonnell

Donald McDonnell

Donald P. McDonnell, Ph.D., is the Glaxo-Wellcome Professor of Molecular Cancer Biology and Chairman of the Department of Pharmacology and Cancer Biology at Duke University School of Medicine. In addition, he serves as Co-Director of the Women’s Cancer Program within the Duke Cancer Institute.

Dr. McDonnell obtained a Degree in Biochemistry from the National University of Ireland (Galway) in 1983 and a PhD from the Baylor College of Medicine, Houston, TX, in 1988, under the mentorship of Dr. Bert O’Malley. After three years in industry at SmithKline and Ligand Pharmaceuticals, he moved to Duke where his work has focused on the genetic and pharmacological dissection of the nuclear receptor signal transduction pathways. The insights from this work have led to the discovery and development of novel estrogen and androgen receptor modulators, some of which have advanced to the clinic and are being evaluated as treatments for breast and prostate cancers and a variety of endocrinopathies.
Dr. McDonnell has received numerous investigator awards; the most notable being the Roy E. Greep, Weitzman, and Ernst Oppenheimer Awards from the Endocrine Society, ASPET’s John J. Abel Award, the Pharmacia-ASPET Award for Experimental Therapeutics, the NAMS SERM Research Award and the Robert Ruffolo lifetime achievement award in pharmacology. He is an Honorary Fellow of the Royal College of Physicians, Ireland, a member of the National Academy of Medicine, and a Komen Scholar. Dr. McDonnell has published over 275 articles on the molecular pharmacology of nuclear hormone receptors. Currently, he is deputy editor of Oncogene, and sits on the editorial board of several journals. He also serves as a board member of the North Carolina Triangle to the Coast chapter of the Susan G. Komen Foundation.


Adam [00:00] Researchers are constantly searching for new and better ways to treat breast cancer. Advances over the last 40 years have increased survival and improved quality of life for people diagnosed with breast cancer. And this is an especially exciting time in metastatic breast cancer research. Many new treatments for metastatic breast cancer are under study and treatment is improving. To tell us more about the emerging areas of breast cancer treatment, today on the show, I have Dr. Donald Donnell. Donald, welcome to the show.

Dr Donnell [00:30] Oh, thank you for having me on today.

Adam [00:31] I’m really excited to chat with you. So, before we dive in, just give us a little bit of information about yourself. Tell us what you’re about.

Dr Donnell [00:38]  I’m a breast cancer researcher. All of my research is focused on developing new therapies and really in the last 25 years, my group is particularly focused on trying to develop therapies for late stage or metastatic breast cancer. I came to this field kind of an interesting way. Everyone has their story. Actually, I think mine is particularly funny and interesting. I met my wife in 1978 at a dance and the night of that dance was the night that her mother had been diagnosed with breast cancer. And at that time I was on my way with a scholarship to study marine biology. But after I got to know the family and got to know my wife’s mother, it became clear to me that my interests lay much more in doing biomedical research than doing marine biology. Changed my scholarship changed my major and started off a career in breast cancer research, moving to Houston to study with Bert O’Malley down in Houston, who’s kind of the grandfather or the godfather of a hormone action in breast cancer. And using that information then started off working between academics and industry taking, you know, mechanistic insights that we’ve learned and how hormones work in breast cancer to the latest and most contemporary drug screening technologies to advance the field. And so that’s kind of my whole personal history, how I got into it and where I’m doing, why I’m doing it now.

Adam [01:52] So that’s fascinating. So, so I’m really glad you went to that dance. Did you dance at the dance or did you stand on the side?

Dr Donnell [02:00] I danced at the dance, but it did take a little bit of coaxing.

Adam [02:05] I share that sentiment. I share that sentiment well. Well that’s great. Well, let’s dig in. What are some of those promising new treatments for metastatic breast cancer?

Dr Donnell [02:14] Yeah, so to understand what the promising new treatments are, I think it’s fair to go back and just look at the point where we came from. Okay. I’d hate people to forget that we’ve made a tremendous amount of progress, as you said, in the last 40 years. And I think that they have basically held the foundation for our current advances. So let’s go back just to approximately 1978. I’m not going to go through the whole history, but go back 1978 when we really had the first hormone therapies approved for breast cancer. At that stage we thought there was really one type of breast cancer, breast cancer. Hormone therapies came along. They showed to be very effective in late stage disease, delay in progression considerably and in some cases preventing recurrence of the disease. That that was a major advance, but one of the things we found was not all patients responded to endocrine therapy and there were two reasons for that and that was because there were more than one type of breast cancer.

[03:07] We now know that only one of the three major types of breast cancer respond to endocrine therapies. Well that was fantastic because that’s a major advance. What it did was, it started the whole field of precision medicine and we discovered that breast cancers that have a particular protein called the oestrogen receptor are most likely to just respond to endocrine therapies. So increasing the chance that a person with that type of breast cancer is going to get a positive response. The flip side of unfortunately was that there were other types of breast cancers where we didn’t have therapies, but then came along another major drug called Herceptin and Herceptin targeted 10 to 20% of breast cancers. It targeted a protein that was expressed on the surface of breast cancers. So now we have two subtypes of breast cancers, at least have targeted options.

 [03:54] The third type, which is called triple negative breast cancer, which we’ll talk a little bit later on has still been a very tough nut to crack. Advances have been made recently in immunotherapy, which we could talk about in a few minutes, but we really don’t have the targeted therapy type approach for that type of breast cancer right now. But recently, only in the last year, we made really significant progress in that disease. And the platform that we’ve, we’ve established now is different in the three different types of cancer. What I want to do, just if you want, the majority of the time is focus on that area of cancer, which I’m probably most familiar with. And that is the oestrogen receptor positive breast cancer, which is about 70% of all breast cancer patients.

Adam [04:36] That seems like that’d be a good one to focus on then.

Dr Donnell [04:38] Well it’s the primary… We can talk about the others, but this is the one that I have focused my research on. So I told you endocrine therapy, the first endocrine therapy that was approved was discovered by Craig Jordan while he was working as a postdoctoral fellow at AstraZeneca was then called ICI. And this was the first, if you want oral pill that you could take that targeted a protein in a breast cancer that reduced, stopped or reduced the growth of a breast cancer.

Adam [05:03] Wow.

Dr Donnell [05:04] Interestingly enough, okay, that drug, and this is a nice story, was actually a failed oral contraceptive. It was not actually made for breast cancer, in fact there was people called it the whoops drug because it failed so badly as an oral contraceptive that basically people were having multiples births.

Adam [05:22] Wow.

Dr Donnell [05:23] And so you can imagine that switching it from a contraceptive to a breast cancer therapy was kind of an intriguing endeavour but Craig successfully did that.That set the stage. And so now in the interim, what we’ve been doing is we’ve been progressively building better and better and better endocrine therapies. What has changed though say in the last 10 or 15 years, is that we’ve taken a step back. And rather than just developing a new Tamoxifen, that was what that drug was called, we’ve actually looked at how the oestrogen receptor works in these cancer cells and tried to exploit that information to develop new drugs. And what was really found primarily by the work of two different groups, Bert O’Malley’s group in Houston and Benita Katzenellenbogen, this work in Illinois, both Coleman scholars, they discovered that the oestrogen receptor in some breast cancers can work without oestrogen.

Adam [06:17] Really?

Dr Donnell [06:17] And so what they figured out was, is that really what they set the stage for was for a type of drugs, which we now call oestrogen receptor degraders. So these are drugs that bind to the oestrogen receptor, degrade the receptor, and when the receptor is not there, now it can’t work.

Adam [06:33 Right?

Dr Donnell [06:34] There was one drug empirically of that class, which is now approved called Fulvestrant, a fantastic drug. It’s got some pharmaceutical problems, but it’s a fantastic drug and it’s the very first of these new class of drugs that bind to the receptor twist it into a shape that the cell thinks it’s denatured and it gets rid of the protein. Now, this drug Fulvestrant, which was approved probably about 10 years ago, reinvigorated interest in these, in this class of medicines called endocrine therapies. Fulvestrant is a pretty difficult drug to take. It’s gotta be taken by injection. It’s phenomenally successful, but our groups and others then said, well, let’s try and figure out how to that drug works and let’s make better drugs.

[07:16] This new class of drugs, which is all -there are now 11 of this class in clinical trials, are called selective because they selectively destruct the receptor in the oestrogen selective oestrogen receptor degraders. Our group actually discovered the first drug of this particular class called [07:33 Taxol.] That drug because of patent issues, never made it all the way to approval studies to regulatory studies, but now there are drugs that have capitalized on that information, on that scaffold to develop new drugs. So in that one pocket there, endocrine therapies, as I said, there are 11 that’s 11 trials that I know about. There could be a few others that I don’t know about.

Adam [07:57] Wow.

Dr Donnell [07:58] In fact, I’ll tell you how advanced I think we are in endocrine therapies. I have stopped my group developing anymore because I think we’ve done as good as we can for the moment until such time as we see clinical readouts of these trials.

Adam [08:11] Right. Okay. How do these new treatments and new therapies, how do they help to limit side effects that allow metastatic breast cancer patients to live longer and better quality of life?

Dr Donnell [08:22] Yeah, that’s actually a very good question. So , I think I kind of indirectly introduced you to that a few minutes ago by telling you that the one drug, the very first drug of this new class is phenomenally effective, but it’s really a difficult drug for patients to take. And so my group decided that, and I’m not the only one, this is not something particularly insightful on my behalf, that an oral drug that can be taken once a day that would not have some of the side effects as some of these drugs have would be the way to go here.

[08:55] And so we’ve known for years that inhibition of the oestrogen receptor is a good thing. Now what we’re learning is inhibition with drugs that don’t cause massive side effects are the way to go.

Adam [09:06] I see.

Dr Donnell [09:07] It is anticipated that the most modern drugs, most contemporary of these drugs. They may cause hot flashes patients, that’s unfortunately a necessary side effect of oestrogen withdrawal, which these things do in women. But they’re unlikely to have some of the other sequelae associated with the earlier drugs in this class. That’s important because in metastatic breast cancer, it’s now apparent from most recent studies that we really have to keep women on endocrine therapy, most women for long periods of time, minimally five years, and those women who are at particularly high end risk, 10 years or even more. So you really need to have a drug that’s, and I don’t want to – the word loosely, but palatable one drug that the cure is not worse than the disease right?

Adam [09:51] Right. Yeah, I love that. And so related to sort of these clinical trials can you tell me some exciting clinical trials that are designed to sort of better understand metastatic breast cancer?

Dr Donnell [10:03] Yeah, so, actually before I do that, if you don’t mind, I don’t want your listeners to walk away thinking that’s the only class of drugs.

Adam [10:10] Sure.

Dr Donnell [10:11] There are one or two more. And the reason I need to tell you that is because what’s most exciting now is the combinations. So before our interview I just had a quick look to see how many, not too many trials, but how many new drugs are actually being tested in patients with metastatic breast cancer. And just a very quick look, I was able to come up with a list of 180 drugs.

Adam [10:31] Wow.

Dr Donnell [10:33]Now some of these are going to be in very small companies, very small clinical trials, but that just tells you first of all that the breadth of the ideas, and it also tells you that what I’m telling you is really the tip of the iceberg, right? So I’m telling you about endocrine therapies in one pillar. Now I’m going to tell you about what I believe is probably one of the most significant advances in the treatment of metastatic breast cancer. And that is a class of drugs called CDK4/6 inhibitors. These are drugs that inhibit a very, very important cell cycle checkpoint in cells. The first developed was a drug called Palbociclib. There’s now two other drugs, Ribociclib and a Abemaciclib, from Pfizer and Lilly and Novartis. They’re all, they all target the same target. They have different off target effects, but ultimately they all work at essentially in the same way they have revolutionized the treatment of metastatic breast cancer.

[11:25] We don’t absolutely know why they’re so effective. One reason we believe is that they’re effective because they synergize, very well with endocrine therapy for the most part now in the metastatic setting, most patients are put on endocrine therapy. If they’ve progressed, they’re put on endocrine therapy plus a CDK4/6 inhibitor and now there’s even a move to move forward and give patients right at the outset to give them the CDK4/6 inhibitor and an endocrine therapy.

Adam [11:55] Gotcha.

Dr Donnell [11:55] But patients, you know, obviously like everything else, there’s patients who really do very well on those patients. And then there are patients who progress for those patients. Now, at least in the field of oestrogen receptor positive breast cancer, we had the exciting results earlier this year of the approval of what’s called a PI-3 kinase inhibitor. And that’s used now in patients who have blown through endocrine therapy, Palbociclib or one of the other CDK4/6 inhibitors and then they go onto this either alone or still within combination with those drugs. So me just picking on those three, it’s really doing a disservice to the whole field, but they’re the ones that I think that I’m most excited about individually and in combinations right now.

Adam [12:40] Okay. Wow. That’s fascinating. And so like you said, there’s a lot of information out there. I would imagine there’s even more out there. I mean, how can someone that’s diagnosed with metastatic breast cancer find out more about new emerging areas of treatment and clinical trials?

Dr Donnell [12:57] The internet is a very daunting place and as most of us know if you have a pain anywhere, you can look it up and you can find some website that will tell us exactly what we need to do. For all of my friends and colleagues actually, to be honest with you, I refer them to either one of three sources for breast cancer, if they’re  breast cancer patients, I really refer them to the Komen sites.

Adam [13:21] Right.

Dr Donnell [13:22] Komen is a national organization that is incredibly focused on its mission to eradicate metastatic breast cancer. And I find that the website that they have outlining not only the new therapies but also how to contact your physician, how to talk to your physician, how to enroll in clinical trials. I find it very user friendly. And I refer friends who call me all the time to that. Of course there’s the American Cancer Society AACR has sites as well, but they’re broad and they’re are definitely good as well, but sometimes the larger sites are a little bit hard to navigate your way through. And then of course, information from the National Cancer Institute. There are many other good breast cancer organizations. I happen be a Komen scholar. So I read that site quite a lot and actually contribute some material to it as well. So I find that to be very useful.

Adam [14:11] I love that. So talk just a little bit more about how has Susan G Komen helped to impact and shape the breast cancer research over the last 35 years?

Dr Donnell [14:21] Yeah, so first of all, the nice thing about Komen is that it’s a very focused organization. Obviously by definition it’s focused on breast cancer, but really in the last, you know, half a dozen years or so it is really focused on metastatic breast cancer. I don’t want to be flippant, but you know, a primary tumor is usually resolved by surgery. Problem is, is that it’s the metastatic disease that basically kills people. And so they have been singularly focused least in my mind in their research efforts on developing, not just research that treats metastasis, but also research that prevents metastasis from the primary lesion. They also have a focus, which I really like on junior investigators and it hasn’t forgotten about us old gray hairs either. But what it has done is it’s provided a career catalyst awards for people who are at the early stages of their career, who are really looking to focus at least some of their research in breast cancer research.

Dr Donnell [15:21] And then there’s junior research awards to trainees which are post PhD but not yet ready to start up their own labs. And I think that funding the next generation of investigators with a focus on metastatic cancer has been a major draw to me, to this organization.

Adam [15:37] Wow.

Dr Donnell [15:38] The other thing that they’ve done, which I have to thank them for is that they really do allow investigators to think outside the box. And I can say that experience. I had a project that I submitted to Komen about six years ago. We had decided that what we wanted to do is develop strategies to see if we could harness the immune system to target cancers. Anyone who looks at that, any, even the [16:01 unclear] will see the tagline that immunotherapies don’t work very well in breast cancer. And there’s two approaches you could have from that point.

 [16:10] One is, “Oh boy, okay, they don’t work. Let’s not do that.” Or two find out why they don’t work and see if you can harness that information to make immunotherapies work. Well that project was funded by Komen, which was great. And we just actually in that work identified a new enzyme target. We’ve got drugs through this target and we believe that these drugs can remold the immune system within the tumor to actually increase tumor immunity. And now we’re embarking on projects through more conventional funding mechanisms to get the next phase of those studies funded. But that project I doubt would have even got a second look through the conventional funders, but Komen funded it. And I, talked to my colleagues over and over again. I hear that theme resonating. And then finally they have a program called the Komen scholars. And the Komen scholars are, it’s a mechanism where they get a community of breast cancer researchers, breast cancer physicians and translational researchers together to provide information and how to direct the foundation. And that’s probably where this singular focus on metastatic breast cancer came from.

Adam [17:18] Wow, that’s fantastic. It sounds like you’re doing a lot of really great work and really helping a lot of people. I really applaud you for your work and appreciate the contribution that you’re making to the community.

Dr Donnell [17:28]  Thank you very much.

Adam [17:29] Well, this was great. Donald, I really appreciate your time and maybe I can have you back on the show again sometime?

Dr Donnell [17:34] I really enjoyed it and thank you very much.

Susan G. Komen launches the MBC Fund!

Susan G. Komen is proud to launch the “MBC Fund” specifically designed to spur scientific discoveries and support those women and men living with Metastatic Breast Cancer, building on Komen’s $210 million investment in metastatic breast cancer research. For more information on the MBC Fund and how to support it, visit www.komen.org/MBC.

Into Thy Heart by Ivan Chew. Ad music is Blue Skies by Silent Partner.  The Real Pink podcast is hosted by Adam Walker, produced by Shannon Evanchec and owned by Susan G. Komen.