A Closer Look at Metastatic Breast Cancer with Dr. Robert Schneider
By BCRF | July 3, 2018
By BCRF | July 3, 2018
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Most women who die of breast cancer die from metastatic disease, the spread of tumor cells to different parts of the body. Metastasis often results following treatment failure, but it also can occur decades after what was thought to be successful treatment. Currently, no curative therapies exist for metastatic breast cancer. But today, the race to develop effective treatments for this disease is a key focus of some extraordinary research, much of it centering on cancer cells’ protein synthesis machinery and a protein called mTOR. What’s the status of this research – and what might some practical outcomes look like? I just had an incredibly thoughtful conversation with Dr. Robert Schneider. He’s the Associate Director of the NYU Cancer Institute, Director of Translational Cancer Research, and Co-director of the Breast Cancer Research Program at NYU School of Medicine. He’s also a BCRF Investigator since 2002.
Chris Riback: I'm Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation, and conversations with the world's leading scientists, studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.
Most women who die of breast cancer die from metastatic disease, the spread of tumor cells to different parts of the body. Metastasis also results following treatment failure, but it also can occur decades after what was thought to be successful treatment. Currently no curative therapies exist for metastatic breast cancer.
But today, the race to develop effective treatments for this disease is a key focus for some extraordinary research, much of it centering on cancer cells, protein synthesis machinery, and a protein called mTOR. What's the status of this research, and what might some practical outcomes look like?
I just had an incredibly thoughtful conversation with Dr. Robert Schneider. He's the associate director of the NYU Cancer Institute, director of translational cancer research, and co-director of the Breast Cancer Research program at NYU School of Medicine. He's also a BCRF investigator since 2002.
Before my conversation with Dr. Schneider, though, one last item and ask from me to you. I hope you like these Investigating Breast Cancer conversations, and if so, I'd appreciate if you'd take a moment, go to iTunes, and if you're so moved, leave a five-star review. The ratings really matter. They go a long way to helping other people find the podcast. Thank you for considering my request. Okay, that's it. Here's my conversation with Dr. Robert Schneider.
Dr. Schneider, thanks for joining me. I appreciate your time.
Dr. Schneider: Pleasure to be here.
Chris Riback: So, I want to start with an extraordinary statistic that goes, really, I think to the heart of your research, and if it doesn't, of course, you'll let me know, the fact that most women who die of breast cancer die from metastatic disease.
Dr. Schneider: That's correct.
Chris Riback: Is that fact sufficiently understood?
Dr. Schneider: No. It is absolutely correct. It is metastatic disease that kills us, whether it's breast cancer or most other forms of cancer, and it is by far and away the most poorly understood, and the one for which there is the greatest number of exclusions in clinical trial. It's actually quite rare, in clinical trial, to be able to include metastatic patients.
Chris Riback: And why is that?
Dr. Schneider: Because when testing new drugs, the metastatic patient population, which is the one most at risk, of course, for death, are the ones where it's hardest to achieve a real effect. So, it is really a problem with the drug approval process, in this country and actually throughout the world, in that one has to show quite a significant effect to get approval, and yet that's not the population with primary cancer that we would typically be treating with these drugs.
Chris Riback: And in fact, to make it even more complicated, I would think, the thing about metastasis is that it not only can occur following treatment failure, but also can occur decades after what was thought to be successful treatment. Is that right?
Dr. Schneider: That's absolutely correct, particular for hormone-responsive or hormone-receptor responsive disease, so ER+ breast cancers, which are the majority of breast cancers, 80% or so of breast cancers, can occur at any point post what we thought was curative therapy. And that's what makes it particular tragic. So, 20 years later, a woman who was actually no longer thinking about her breast cancer has a recurrence. It's about 60 to 65% of all breast cancer mortality, metastatic disease, late recurrence, ER+ breast cancers.
Chris Riback: Did that inspire you to get into this area and to focus on this area, or did that happen through different means?
Dr. Schneider: It actually did. You know, many of us that started our research careers and clinical careers in other areas have moved over to breast cancer because of personal tragedy in our family lives, and that was my motivation. The first half of my career, I was a virologist, working on viruses that cause cancer, such as liver cancer, by hepatitis D virus, and faced with exactly that dilemma where it was extraordinary to me that in the case of either very early breast cancer, where the cure, quote, "Cure," was double mastectomy, or in the case of the metastatic setting, that we knew almost nothing about the cause of disease, and we had no real treatments.
And I came in one day and turned my back on what was a really rich research career, with many NIH grants, and said, "No, today I'm going to be a breast cancer researcher." And that was some 20 years ago, turned my back on it, and I have never looked back. I'm delighted that I have, and I'm having an impact.
Chris Riback: Yes. You are, and I want to ask you about some of that impact that you've had over the years, but let's talk about your research and your efforts to develop effective treatments. What is mTOR?
Dr. Schneider: mTOR is protein kinase, so it's a protein that regulates many metabolic pathways within cells.
Chris Riback: Yes. Tell me what that means.
Dr. Schneider: So, when one consumes sugar, or you eat, or you're deprived of nutrients, mTOR is the central gatekeeper and regulator of how your cell is able to respond. Whether that cell shuts down and becomes basically a resting cell or whether that cell becomes stimulated and proliferates, all of that is controlled by mTOR. And the way it does that, in part, is through the control of how we make proteins.
Chris Riback: And what does that have to do with metastasis of breast cancer?
Dr. Schneider: So, one of the most difficult parts of understanding metastasis is understanding how a metastatic breast cancer cell is able to reproduce itself and spread throughout the body, in an environment in which it's starved for oxygen and starved for nutrients, in which most cells would normally be shut down and stop proliferating, and in many cases, they would die. The metastatic breast cancer cell has solved that problem by increasing the activation of the kinase mTOR, and tricking the cell, basically, into believing that it has lots of nutrients and oxygen, and so it keeps on proliferating and spreading. So mTOR, therefore, has become a very major focus of our research and that of many others.
Chris Riback: So describe that focus for me. How do you ... I don't know if ... How do you un-trick the process? How do you think about affecting mTOR or affecting the process in a way such that the effects that it otherwise would have don't occur?
Dr. Schneider: That's an excellent question, and it really goes to the heart of how do we translate what we do in the lab to having an impact on the lives of patients. And this is an issue that I face all the time. I made the decision 20 years ago, that the only way to do that is through the creation of new therapeutics, and the reason for that is because we know that magic doesn't work, and we learned that about 300 years ago, so it's only through the development of new therapeutics, new types of drugs, that we're able to actually manipulate the cancer cell. And in the case of mTOR, there are a series of drugs now that have been developed that can shut down mTOR in various ways, and they're having some efficacy in the clinic, but we need to, at a much greater level, really begin to understand how cancer cells are able to continuously find ways to circumvent the inhibition of mTOR, and that's a large part of what we work on.
Chris Riback: You used a word at the beginning of that answer. You talked about translate, or translating.
Dr. Schneider: Yes.
Chris Riback: You're the director of translation cancer research at NYU.
Dr. Schneider: And drug discovery.
Chris Riback: And drug discovery, a whole bunch of stuff, but I'm just focused because I saw that, and so I did a little bit more reading on translational science. And given what you said earlier as well, about getting ... that the personal reasons and what motivated you, that's really the key, I guess, isn't it? That translational science is taking the research, and that scientific and those discoveries, but then translating them and applying them to human lives, to how we live our lives.
Dr. Schneider: Yes. It absolutely is, and you know, ironically, it is the way research began. So if you go all the way back to the early days at the turn of this past century, Salk and Sabin were creating vaccines for polio virus, and while they were interested in the mechanisms by which viruses like polio virus cause disease, they were also interested in how to prevent that. And then over the years, science has seemed to diverge between groups of scientists that do basic research, and I do basic research, and those that just translate it. And the reason is because it's really hard to do both, because you have to be a master of basic research and all of the molecular understanding that comes with that, and at the same time, you really need to understand the disease itself and how to actually develop drugs and move them into the clinic as well.
You know, so it's somewhat overwhelming. It does take some time to really begin to master both of those fields. At the same time, I believe that for those of us that have been provided the gift and the responsibility to be in major medical centers, that's what we have to do.
Chris Riback: And I would assume, as an outsider, that there's some kind of positive circular effect that occurs. I would think that what you see in human life goes back and affects how you do ... maybe some insights or informs your basic research, which then must necessarily inform the work that you do with actual patients.
Dr. Schneider: It actually does, and in fact, even for the graduate students in my lab, I have patients, patient advocates, survivors come to the lab and visit and tell their stories. And I have them come to clinic as well, the students, and postdocs, and others as well. It is why we're here. It's enormously satisfying. It's an enormous motivator, because it's no longer abstract. And I say to them, "You come and you tell this 32-year-old woman with two young children that we have nothing left to offer her. You'll want to go right back in the lab and start working on that right away," and that's why we do it.
Chris Riback: Yes. That's fair. That's just incredibly powerful, and it's a, I'm sure, huge motivator.
Dr. Schneider: Yes. We don't have a lot of time on this Earth, right?
Chris Riback: No.
Dr. Schneider: This is a gift that we have, to be able to do science and translate it.
Chris Riback: Yes. What a wonderful point of view. I couldn't agree more. Tell me about the approaches that you are testing now, or some of the trials or research that you have going on right now.
Dr. Schneider: Sure. So, I have built on our understanding of how protein synthesis is controlled in the metastatic breast cancer cell. So we've been able to show over the years, and in more publications, some of which will be coming out soon, that they have ... cancer cells, in the metastatic setting, have enacted specialized programs for making certain that they can make the proteins they need for their survival and their spread. So now understanding those, we've gone back in and started developing new therapeutics to attack specific mechanisms, so that rather than utilizing toxic drugs like common chemotherapies, we're utilizing designer drugs that cancer cells seem to have no capacity to circumvent.
So we're now moving some of those from the laboratory bench. We've moved them into animals. In other cases, we've moved from animals into humans, and we've done that in several areas. One of those is in immuno-oncology, so we've developed several new immuno-oncology agents that we're hoping to have in the clinic next year that will eliminate, to a large extent, the stealthiness of metastatic breast cancers and others, and at the same time, attacking within the cancer cell, some of the unique mechanisms that they have developed to produce their own proteins.
And in that case, we're actually doing it in a very designer, specific fashion, and that is that we actually have structures of these proteins, and working with computational chemists, we're actually fitting molecules into those structures and having them synthesized. That actually is a much quicker way to develop new therapeutics, new types of drugs, than screening millions and millions of compounds for a specific inhibitor. We now have computational power to do this.
Chris Riback: It's incredible, and I've had the privilege to talk with some of the computational researchers and scientists, and yes, the work that they're doing, and the speed to market if you will, it's not really the right term-
Dr. Schneider: That's right.
Chris Riback: ... but just the way it speeds up the process, yes, seems fascinating. The drugs that you would potentially develop based off of this research, and maybe even some of the ones that you've developed historically. How do they work with chemotherapy? Does it reduce ... We all hear about chemotherapy as being one of the key processes, obviously. How do the drugs work in conjunction with that?
Dr. Schneider: So what we have tried to achieve in certain of these drugs is to be able to lower the levels of chemotherapy that are required to achieve the death of metastatic cancer cells. That's one of the keys, so they are now in animal models where we've been able to do that, and to reduce the toxicity quite enormously. So what we have shown is, by inhibiting mTOR by only 20% or 30%, which is extremely well tolerated, we're able to reduce the amount of chemotherapy that's required to achieve what is a really significant effect on metastatic cancer cells, particularly breast cancer cells.
The next step is to get this into the clinic, and to be able to conduct clinical trials where we show we can achieve the same effect without all that toxicity, right? It's the toxicity that people fear when they are faced with having to be treated for, for example, hormone receptor negative breast cancers.
Chris Riback: Yes. Yes, and what a difference, you know, going back to the translational discussion and the impact on everyday life, what an impact that would make to be able to reduce that toxicity and improve a person's ability to recover.
Dr. Schneider: That's right, and the other part of that that we should not lose sight of is that we treat a lot of breast cancer, of course, without chemotherapy. So many women are treated with hormone receptor positive breast cancer, with aromatase inhibitors and with tamoxifen, so inhibitors that block endocrine function. The problem, once again, is that roughly 50% of the time, those cancers come back, as we started to talk about at the outset of this discussion. They'll come back 20 years later, now, and they're no longer sensitive to endocrine inhibitors.
So much of our work is also designed to be able to make them sensitive again to those endocrine inhibitors, which are not toxic, for the most part, reasonably well tolerated, and we've been working on that, actually, quite diligently, and we now are prepared to move forward to the clinic with a drug combination, again based on mTOR, that has reversed endocrine resistance.
Chris Riback: And you mentioned going back 20 years. I wanted to ask you as well about ... This is about 10 years ago, I think, research of yours, and extraordinary discovery, but I'm interested in how it has affected your research since. What is the EIF4G1 gene? And if I'm saying that wrong, please tell me.
Dr. Schneider: No.
Chris Riback: Yes, so what is it, and what does it have to-
Dr. Schneider: What an awful nomenclature. I can't be blamed for that nomenclature.
Chris Riback: You didn't do the branding on that?
Dr. Schneider: I didn't do the branding on that.
Chris Riback: Okay, well we'll [crosstalk 00:17:40]
Dr. Schneider: So those are specific factors that carry out protein synthesis, and indeed, we have a paper that will be coming out, hopefully in the next several weeks in a major journal, one of the premier journals, showing that we've discovered yet another novel protein that carries out protein synthesis, and is absolutely essential for metastasis, and so you can bet, right now, we are heavily invested in drugging that protein right now.
So, at the molecular level, every type of biosynthetic pathway within our cells that enable us to make our DNA, and our RNA, and our proteins, and our carbohydrates, and our lipids, our fats, every one of those is extremely complicated and directed by a very large number of proteins, thousands and thousands of them, and we keep discovering new proteins every year.
So, these factors, we have been able to demonstrate, do not function like a light switch. They're not on and they're not off. In fact, what they have are specificities, so certain types of genes that are required, for example, for the survival of a cancer cell and its ability to metastasize throughout the body have a much greater requirement for these factors than do the average genes that are functioning just to keep cells proliferating, for example, and metabolizing. And that was a real breakthrough, because what that did was open the door to understanding that we have selectivity in these pathways, and we can drug them with that understanding.
Chris Riback: How did you get into all of this, and by all of this, I mean going way back? Where did you grow up, and for you, was it always science? Did you ever think, at one point, that perhaps you'd be a fiction novelist instead?
Dr. Schneider: Yes. I actually wanted to be a stand-up comic, but that wasn't going to work out. I grew up in a science family. My father was a chemist, uncles ... one uncle was a chemist, another was a physicist. And I tried to get away from it, actually, although I've always loved science, and I was a philosophy major in college, and ultimately, it pulled me back in, and I wound up having a dual degree in philosophy and biochemistry, and I enjoyed it.
I was always drawn to trying to understand how things worked, and I was so intrigued by the ability to be able to change my universe around me through my understanding of science, whether it was to be able to make inks and glues, or how electricity worked, it really provided the ability to change the world that you lived in. So for me, it was just a natural continuation. I will say my philosophy background has proved to be important as well, because it trains your mind to think in a very more abstract way, and so that combined with science, I think, was a great way to start.
Chris Riback: Yes. Your philosophy background absolutely comes across in your ... not just your demeanor, but your thoughtfulness, and it makes sense. It makes sense why you do both the basic research, as you discussed, and then the translational work, that would seem to me that for somebody crazy enough to marry philosophy and science, you seem to have carried that out.
Dr. Schneider: Many more than you think, actually. They actually do work well together. So do the arts. That's why there's so many people that are so talented in the arts that also are scientists.
Chris Riback: That's terrific. That would be an interesting series of conversations, and just to close out ... I mean obviously, you get and have earned support from a number of areas. What role has BCRF played in your research?
Dr. Schneider: Yes, you know, if it wasn't for BCRF, none of this would have happened. None of this would have taken place. None of these breakthroughs would have occurred, and I say that in all seriousness. While I am indebted to the National Institutes of Health, and I'm well supported by them, I have four NIH grants right now, it is the BCRF that has enabled me and everybody else that's supported by that organization to think really creatively, to take the kind of risk that you could never take by conventional funding.
You know, the motto at BCRF is basically, "Do something really smart. Take a risk. Take a chance," and that's what we have all done. It has enabled us to generate the kinds of data based on ideas, and not crazy ideas, but really thoughtful ideas for which we don't yet have any evidence, to really take that chance, and know that next year, they'll continue to support us, even if in that given year, we did not make great progress, simply because they know that we're taking a risk and trying to think about the problem of breast cancer in a very different way.
And I will say, every one of my major breakthroughs has been funded by the BCRF and then later picked up by the NIH, that allowed me to then more fully develop it, and then ultimately picked up by companies, whether it's a company I helped start or a larger pharmaceutical company, to then bring that forward into the clinic.
Chris Riback: That's terrific, and it's great to see how it can grow and how it can grow from an idea to actual research, and then into the market itself.
Dr. Schneider: Yes.
Chris Riback: Dr. Schneider, thank you. Thank you for your time and thank you-
Dr. Schneider: Thank you.
Chris Riback: ... for the risks that you've taken.
Dr. Schneider: Thank you so very much.
Chris Riback: That was my conversation with Dr. Robert Schneider. My thanks to Dr. Schneider for joining, and you for listening. To learn more about breast cancer research or to subscribe to our podcast, go to bcrf.org/podcasts.
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