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Can life change with a single letter in the mail? For my guest today, it did, and subsequently, so did the lives of millions of people with various forms of cancer, including breast cancer.
The letter in question came from the National Cancer Institute in 1977. The recipient was Dr. Susan Horwitz. The result: the creation of one of the most important cancer drugs that come from a natural product: Taxol, which is isolated from the yew plant. Today it is given to over a million patients.
As you’ll hear, Dr. Horwitz work – indeed, her incredible curiosity – didn’t end there. She has continued to investigate new cancer treatments that leverage natural products. Why?
Take triple negative breast cancer. By definition, it’s among the most challenging cancers to treat, comprising some 15-20 percent of all breast cancers. These aggressive tumors are treated with a cocktail of chemotherapy drugs. And although many patients have excellent survival following treatment, some patients with specific types of triple negative breast cancer have an incomplete response or even a relapse after a period of remission.
Making them even more difficult: Triple negative breast cancer tumors are frequently resistant – or become resistant – to a variety of drugs, increasing their potential to spread to other tissues – a process called metastasis.
To address these challenges, some scientists have screened novel chemotherapy drugs against triple negative cells to identify those with superior activity and less toxicity than conventional therapy. The goal: Find new therapeutic options — new drug candidates – that they hope may lead to targeted therapies and new combination approaches to counter drug resistance and improve outcomes for patients with aggressive breast cancer.
How does this process work? What progress has been made? How hopeful do the outcomes seem? Dr. Horwitz is the one to ask.
Dr. Horwitz is a Distinguished University Professor and the Rose C. Falkenstein Chair in Cancer Research at the Albert Einstein College of Medicine in New York.
Among her many honors: The Warren Alpert Foundation Prize from Harvard Medical School; American Cancer Society’s Medal of Honor; the American Association for Cancer Research Award for Lifetime Achievement in Cancer Research. Most recently, Dr. Horwitz earned the 2019 Canada Gairdner Award, the country’s highest scientific prize. She has served as president of the American Association of Cancer Research, and has been a member of The National Academy of Sciences, the Institute of Medicine of the National Academies, [the American Academy of Arts and Sciences, and the American Philosophical Society,] and others. She also has been a BCRF Investigator since 2007.
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.
The letter in question came from the National Cancer Institute in 1977. The recipient was Dr. Susan Horwitz. The result: The creation of one of the most important cancer drugs that come from a natural product: Taxol, which is isolated from the yew plant. Today it is given to over a million patients.
This was a remarkable conversation, not only for the science discussed, but also the role Dr. Horwitz has played in its history.
Chris Riback: Dr. Horwitz, thanks for joining me, I appreciate your time.
Dr. Susan Horwitz: It’s my pleasure.
Chris Riback: To begin, congratulations. You were recently named one of seven winners of Canada’s Gairdner Award. And by my reckoning, you’re not even Canadian. That’s quite an honor.
Dr. Susan Horwitz: I am not Canadian and it is quite an honor. I’m deeply honored.
Chris Riback: The president of the organization that nominated you, said, and I’m quoting, “Susan meticulously unraveled the mysteries of one of the world’s most important cancer therapeutics.” Do you think of yourself that way? As a sleuth? Do you feel like a medical detective, a scientific Miss Marple perhaps?
Dr. Susan Horwitz: Well that’s exaggerating a little bit. But I do, in a way, think of these as puzzles. Trying to understand, as deeply as we can, how a drug acts to interact with a cancerous cell.
Chris Riback: So, let’s talk about those drugs and that interaction and, you know, of course, having that conversation with you, it’s impossible not to start that conversation with your Taxol work, which involves using natural products to develop treatments. Why natural products? How did get there? I know a little bit about it. I’ve read about this story but I’d love to hear it from you directly, because it sounds remarkable.
Chris Riback: Apparently one day in 1977, you got a letter, I believe it was, or perhaps a call but I think it was a letter, from the National Cancer Institute.
Dr. Susan Horwitz: That’s correct. I received a letter from the National Cancer Institute requesting that I look at the mechanism of action of Taxol. I had never heard of Taxol, to be very honest, and there was only paper in the literature. So you certainly wonder why did the National Cancer Institute call and interact with me. Well, I’ve had a long-standing interest in natural products as a source of new drugs for the treatment of cancer. And when they had written to me, I had published on a number of natural products. And by natural products I mean compounds which are isolated from living organisms. That can be a tree, that can be a bush, that can be a sponge from the ocean, it can be from a bacteria. But those were the kinds of compounds I was interested in.
So, I think that’s the reason that the National Cancer Institute wrote to me and as I say, there was only one paper in the literature and that was written by the two medicinal chemists, Drs. [Monroe] Wall and Mansukh Wani who had actually isolated this molecule from the bark of the tree Taxus brevifolia, which is the western yew. Many of us have this tree or bush, actually, in our gardens and that is where this drug originally came from. It was from large trees which grow on the west coast in Washington, Oregon, Northern California.
So when I got this drug, the first thing I, of course, looked at, was the structure. One thing about natural products is that they introduce structures that no chemist would sit down and synthesize. They’re quite unusual. Taxol is what I call architecturally complex. It has many [boots] in it that aren’t seen in other places, in other drugs.
So it was intriguing. And I had a new graduate student at the time, Peter Schiff, and I said, “Well, let’s look at it. We’ll look at it for a month and if it’s interesting, you can use it as your thesis project. If nothing happens, we’ll look for another thesis project.” So that’s how, really, I got into the drug. But after that one month, we knew we had something interesting.
Chris Riback: It was a heck of a month, wasn’t it?
Dr. Susan Horwitz: It was!
Chris Riback: Why natural products? So it’s interesting to me that you already had an interest in that aspect of research and of science and that that was kind of why the National Cancer Institute sent you a letter. I’m curious, do you happen to know? Did they send any other letters out and perhaps you were the first to respond? Or were you the only person they sent the letter to, to your knowledge?
Dr. Susan Horwitz: To my knowledge I was the only person they sent the letter to, but I really don’t know, to be honest. Many people don’t realize how important natural products are, in determining drugs.
Chris Riback: Explain that to me, please.
Dr. Susan Horwitz: Okay, so about 50% of the drugs that Americans take today, are either natural products, a derivative of natural products. Did you know Aspirin for example, which everyone takes some time in their life, for a variety of reasons, originally was from the Willow tree.
Chris Riback: No, did not know that.
Dr. Susan Horwitz: Penicillin, which really was so important, the Second World War and treating diseases, comes from a fungi. The pill which has changed our world, originated from yams in South America. So about 50% of the drugs we take, come from natural products. And I’ve always found that very fascinating and very interesting because it allows you to study not only the chemistry and the biology, but the botany and trying to understand why and how these natural products are produced. And of course, as we reduce our forests, the Amazon, we’re probably getting rid of a lot of drugs which could be important.
Chris Riback: Do you think, was it your background in biology that potentially led you to have that interest in natural products, or was it something else about you or the way your mind words that drew you in that direction?
Dr. Susan Horwitz: Well, a lot of different things of course have come together. I was, when I was a graduate student, I was studying enzyme kinetics, and I thought I would go on and study enzyme kinetics. But, for a number of reasons, I was then looking for a part-time work. So when I got my PhD, so I was able to get a job in a department of pharmacology at Tufts Medical School. I didn’t know anything about pharmacology at that time, really. Pharmacology has changed dramatically in the last 40 years. But I was sort of thrown into it. And I just liked it. I just liked the idea that a small molecule like Aspirin, can take your headache away. So I stuck with it. And rated my personal niche and I thoroughly enjoy it.
Chris Riback: Can I ask you a side question? You’ve said two things on the same, in the same vein that raised just a totally separate conversation or question for me, which is, twice you’ve said that you went through with something or went forward on something that you knew nothing about. Pharmacology, you just mentioned and then previously Taxol, you indicated you hadn’t heard about it. For so many of us, that’s an impossible task. So many of us feel, “Well, unless I’m an expert in something, I can’t go forward with it.” What made you go forward on two, you know, in so many areas that you didn’t perhaps have the exact background on, according to you, but that didn’t stand in your way?
Dr. Susan Horwitz: Well, that’s the kind of person I am. I think that it’s important to explore new things all the time. And when you have an interest in something, and I didn’t have an interest in Taxol, because I didn’t know anything about it, but I was curious. And, you know, it came at the right moment, when I had a new student looking for a thesis. But I do think it’s important for scientists to explore new areas and especially to explore new ways of looking at the same problem. Too many scientists sort of do their PhD thesis over and over again. And you don’t want to be that kind of a scientist. You want to be open to new technologies that are arising every day and you want to take your problem and use it in that technology. So I think that’s important for a good scientist.
Chris Riback: So how does Taxol work? I realize its molecules bind to the microtubules in tumor cells, stabilizing them and ultimately, I believe, killing them. But describe, if you would for me, what is that process like in lay-person’s terms. How does it work?
Dr. Susan Horwitz: Well just like we have a cytoskeleton, our bones, every cell in our body has a cytoskeleton. And a component of that cytoskeleton, a very important component, is the microtubule, because when a cell is going to divide, it’s actually the microtubules that pull apart the DNA, that’s in our nucleus, in our cells, so that each daughter cell, gets an equal amount of DNA.
So the microtubules have to perform exactly perfectly to get two normal cells. And if you take Taxol, which has a very specific binding site on the microtubule, those microtubules are like paralyzed and they cannot pull the DNA apart and you do not get two normal daughter cells. Daughter cells meaning the next generation of cells. And you have a serious problem. And eventually that cell will die. That is what Taxol does. When it binds to that site, it’s a very specific site, and then the cell cannot divide properly.
Chris Riback: And Taxol of course, helps with multiple forms of cancer, ovarian cancer, breast cancer, lung cancer. Were you focused on any particular type of cancer? And you then discovered that Taxol worked across multiple forms? Or you were more looking at cures for, or ways to address cancer at large and these were the-
Dr. Susan Horwitz: I was looking for a way to treat cancer at large. I mean, when you start out with a new drug, you never know what’s going to happen when you put it into a human. So that is the ultimate test, will a drug be useful in a patient that has a malignancy?
Chris Riback: And some of your current work, I understand, focuses on dormancy, the state when cancer cells don’t divide. However, we shouldn’t be fooled, even in dormancy. These cells are doing dangerous stuff, like producing inflammatory proteins, they can make the tumor cells migratory, which of course that’s what is part of what leads to metastatic cancer. Describe for me, what’s the work that you’re doing there?
Dr. Susan Horwitz: Well, we doing two things, we have two projects in the lab, really, that I think are of interest, and which are being supported by the BCRF. One of them has to do with drug development. I mean, I’ve had a lot of experience with Taxol and I’d like to use that experience to try to develop better drugs and we need new drugs, particularly for triple negative breast cancer.
Chris Riback: Yes, why do we need new drugs?
Dr. Susan Horwitz: We need new drugs because, particularly triple negative breast cancer, there are no ways of treating this, except with chemotherapeutic agents and you know, cells become resistant to drugs. This is a very serious problem, one which I’m very interested in. And so we need new drugs to overcome some resistance. We need new drugs to make combinations of drugs and combinations of drugs with immunotherapy and it’s targeted drugs. Many of which also use some of the agents such as Taxol, to deliver these together. So we do need new drugs, with new mechanisms and since I’ve had a lot of experience with Taxol, I’m looking for new drugs that might have similar activities with Taxol, but which would not show cross-resistance. And this is a project that I’m working on with Dr. Hayley McDaid. And also with Amos Smith, who is a colleague from the University of Pennsylvania, who is a synthetic chemist, because he’s working with us and developing new molecules that may be useful for triple negative breast cancer.
We have some metastatic models in cell culture. We look at the ability of our cells to migrate through a Jello, a gelatinous matrix, to see if they have metastases. As I said, you really have to move on from cell culture, but it’s a very good way of screening, looking for drugs that may be metastatic to inhibit metastases. So this is a whole area of drug development which I’m working and trying to use my knowledge that I’ve acquired over many years to help me in developing new agents.
Chris Riback: And, is that one area of work and then was there a second area that you were going to talk about or did that encompass both areas?
Dr. Susan Horwitz: No, I can certainly talk about the second area. It’s something I’m very interested in.
Chris Riback: Yes, please.
Dr. Susan Horwitz: As I told you, Taxol binds, has a binding site on microtubules. Now, we know that microtubules are far more complex than we ever dreamt. And one of the things that makes them very complex, is that there are many different forms of microtubules. We call them isotypes. So there are many different tubular isotypes that make up the microtubule. So we know that a tumor, different tumors, have different isotypes in them. And the question that I’m so anxious to answer, is does Taxol or other molecules that interact with microtubules, doesn’t have preference for some of the isotypes and then not interact with other isotypes? This has been a burning question for me and has been very difficult to answer. But now, we’re able to clone and express the individual isotypes so that my goal is to have recombinant tubular isotypes in the laboratory so that we can study the interaction of Taxol with these different isotypes and this is very exciting. We’re really making progress on this. And I’m able to do this because of the funding that I’ve received from the BCRF.
This is difficult research. It takes time, it takes tenacity. I work with Dr. Chia-Ping Yang on this problem who can look at a very challenging problem and not get discouraged and continue to work on it. And we’re making progress.
So this would really be a wonderful thing. So not just me, but for many scientists who are interested in tubule and the interaction of drugs with different compounds.
So we have to look at tumors and we have to determine which isotypes are in that tumor. And then ask will Taxol interact well with those isotypes? These drugs, Taxol particularly, I’m sure anyone who’s taken the drug can tell you this, has side-effects which are unpleasant. If you use a drug in an instance when you know it is not going to be successful, all the patient gets from this, is the side-effects. So we want to be more specific in who we give the drug to by understanding the different isotypes in the tumor.
So this is a big project. We are making progress, slowly but surely. And I hope to have these different recombinant tubular isotypes to study. Not just for me, but for, you know, the scientific community.
Chris Riback: Yes, you just hit on two points that I hear so frequently in these conversations. One is, the ability not to get discouraged, seems to be a genetic consistency among the top scientists. Because there is, there’s so much room for, and I’ve had some of my guests describe it, it’s not failure. They don’t consider when experiments or research doesn’t work the way they might have hypothesized, they don’t even think of it, necessarily as failure, it’s stepping stones and learning towards the next stage.
Dr. Susan Horwitz: That’s right. But it can be discouraging.
Chris Riback: Well, Yes, I can imagine. But it seems that many of you lack that gene or it’s a recessive gene maybe, at best.
Dr. Susan Horwitz: We try to keep it recessive and we try to keep it recessive for people with whom we work, because that’s really very important to keep up everybody’s spirits in the lab and really believe that progress can be made.
Chris Riback: And so, tying that in, you were discussing how important this research could be, for you of course, but also for other scientists. Translate that then for me down to the patient level. Is this where you are talking about the discovery of new treatments, of different types of treatments and by doing your work, you have the potential to almost feed a family or a big gathering of scientists who then can go and take some of your work and expand on it. Is that how you see it?
Dr. Susan Horwitz: Well I see it in different ways. For an example, we know that 50% of the patients, let’s say with ovarian cancer who get Taxol, respond to it. And 50% do not. And we don’t have any idea why 50% do and 50% don’t. So one thought that I had was the possibility that the isotypes are different in these different patient populations and could that be partially responsible for why some patients don’t respond to the drug? So we already have evidence that one of isotypes, doesn’t interact well with Taxol. We’ve done that in the laboratory. And this could possibly give us, and this is not going to be we cure a 100% by any means, but it gives us an in of more understanding of how to treat patients. And, of course, the development of new drugs, with natural product origin, really can help patients who are resistant to the drugs that are available, or you hope that a new drug that you find, is going to be better than Taxol, with less side-effects. All of these things have to come together.
Chris Riback: Understood and when you say something like, you may not get, you certainly won’t get or might not get to a 100%, one can still imagine if you’re at 50% right now, what does a 10% improvement look like? You know, and when you’re talking about 10% of a big number, even that’s a lot of people. Or 20%, so any, I assume from your point of view, any improvement is improvement and unfortunately, because the denominator is such a big number, the improvement even by small percent, can mean impacting a large number of people.
Dr. Susan Horwitz: Yes, and a decrease in side-effects can really affect a lot of people. So these are the things that we’re working on in the lab and trying to make progress with.
Chris Riback: So if that is a look forward, I’d like to close the conversation, and I don’t usually close by taking a look backward or usually I try to, you know, close by looking forward, that’s generally where these things go, but there’s one more aspect about your personal story that just made me so curious and interested and I’d love to close there. We’ve been discussing, you were a pioneer and that’s my word, not yours, in the use of natural products in fighting cancer. But by my math, you were a pioneer even before that.
Chris Riback: You graduated with a degree in biology in 1958 and then a PhD in biochemistry. I can’t imagine that your field was overflowing with women at that time. What inspired you and what was it like to be a woman biologist then?
Dr. Susan Horwitz: You were right, it was not overflowing with women at that time and I can tell you many stories. When I actually went to Bryn Mawr with the idea that I would major in history, I didn’t come from a family of scientists at all and when I arrived I had to take a science course. That was a requirement. And I thought, “Well I’ll take it the first year and get it out of the way, and then I can study what I like.” But actually, it turned out to be quite different. I took biology, I loved it. I changed my major and that’s, I really enjoyed it tremendously. I majored in biology and minored in chemistry. And as I say, it’s what I wanted to do and then I started looking for jobs actually, after my junior year thinking I would [fly] to Boston, my family was from Boston, I would come back and really there was nothing interesting at all.
I was offered a job at a company to take the dyes from the lipstick and put them in the eyes of rabbits to see if they were allergic to them. And that’s certainly not what I wanted to do.
So I started looking into graduate schools. And, you know, some of the graduate schools that I talked to, I would talk to a professor and after that I’d say, “Thank you so much. Could you tell me where the ladies room is?” And they’d look at me and say, “The ladies room? There may be one down in the basement.” This happened all the time. So the chemistry department just didn’t think about women at that time. And then other places said to me, “Are you sure you want to get a degree in biochemistry? Or maybe you should get a degree in biology and then you could work at a museum.”
So at that time, Brandeis University was starting its biochemistry department. It was brand new. I went there to look at the department, and I was delighted. There were two women on the faculty. This was the very beginning. I was in the first class. Mary Ellen Jones was an assistant professor. She was married, she had children. [inaudible] was also an assistant professor, married and had children. And I don’t mean to say that you can’t be a good scientist if you’re not married or if you don’t have children, but that’s what I was looking for, and I was interested in my own personal life.
And so I was attracted to that. And so I went. And it was one of the best things I ever did.
Chris Riback: And I assume they had a women’s room already built, since they had two faculty.
Dr. Susan Horwitz: That’s right.
Chris Riback: Well, history’s loss and the loss of one more historian was certainly science’s gain. Thank you. Thank you for this conversation and obviously thank you for all the work that you have done.
Dr. Susan Horwitz: Thank you very much. Pleasure to talk to you.
Chris Riback: That was my conversation with Dr. Horwitz. My thanks for Dr. Horwitz for joining in 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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