Among the many challenges with breast cancer and breast cancer research is metastasis when cancer cells break away from a tumor and travel to distant parts of the body. Within this collection of cells is an important minority group, breast cancer stem cells. These cells are ultimately responsible for cancer related death in women with the disease and understanding how they work is central to much of today’s research. At the forefront of that research, Dr. Michael Clarke. Dr. Clarke is a Professor of Medicine at Stanford University and since 2005, a BCRF grantee. He is also the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.
In 2003, Clarke’s lab was the first to identify breast cancer stem cells. Since then, among other findings, Clarke’s team has identified two genes critical for stem cell functions including a gene that regulates normal stem cell dormancy which can drive the unpredictable length of time when tumor cells exist quietly without clinical manifestation. It’s one of the most pressing problems in breast cancer responsible for late relapses. What’s next from Dr. Clarke and his lab? What ideas is he exploring that might help prevent relapse?
Chris Riback: Dr. Clarke, thanks for joining me. Before we get into the specifics, I’m always curious, why research? What was it about scientific research that once upon a time said to you, “This is where I can make a real difference”?
Dr. Clarke: As you can tell from my academic appointment in department of oncology, I’m a board certified oncologist. When I was seeing cancer patients, what I realized is, although we do well and we are clearly making advances in cancer treatment, we really needed to do more. I just realized that by doing research in the end I might have more impact on patients and how they do than I would taking care of individual patients who as a full-time clinician. Luckily, one of my mentors at Indiana was a fellow by the name of Larry Einhorn, who figured out how to cure testicular cancer. I was a fellow with Larry or a resident with Larry actually.
Dr. Einhorn pulled me aside one day and said, “You should really go into academics.” He said, “You should either do bench research or basic science or clinical research.” He said, “Either is equally important, but you should concentrate on one or the other because we need both.” He asked me, “Which one do you want to do?” I said, “Larry, I think I’m a little bit biased towards basic research.” He said, “I totally understand.” Even though Larry is a clinical researcher. He helped facilitate my getting good fundamental basic science training so I could go into primarily bench research, but clearly my bench research is geared to try to understand diseases and breast cancer is one of the major things my lab studies and how understanding basic mechanisms can be used to improve treatment for women with breast cancer.
Chris Riback: To talk about your work today, I think it really helps to understand exactly what you discovered and analyzed starting in 2003. Why was it such a breakthrough to identify breast cancer stem cells?
Dr. Clarke: Let me explain what led to the discovery and what I understood. It actually goes back to my training with Larry Einhorn. When I was at Michigan, I was taking care of patients with testicular cancer. As part of that, I used to give lectures to medical students about germ cell tumors. I was giving a lecture. There’s two types of germ cell tumors. There’s mature teratomas which are benign. As the name applies, they are cancers with mostly mature cells or all mature cells in them. Another type of cancer which is called immature teratoma which is malignant, metastasizes, and behaves as a very aggressive cancer as opposed to essentially a benign tumor like mature teratomas.
I had a patient that I treated using the regimen Larry Einhorn really came up with, who had immature teratoma. Basically, when I treated that patient, his tumor shrunk, but he had residual tumor. When we took that tumor out, it had converted or it was consisted only of mature cells. That patient was cured. That was the teaching point that when you give platinum-based cancers, you can have residual tumor masses. If there’s all mature cells, most patients go on and they are cured. As part of that teaching point, I showed the slide of his original tumor which was an immature teratoma. When I looked at that tumor, what I noticed to my surprise was it wasn’t all the cells that were immature. It was just a minority of immature cells really in a bed of mostly mature tumor cells.
The dogma at that time was that platinum-based therapy caused the cancer to differentiate. What I realized what was probably happening is that platinum in testicular cancer was killing the immature cells and that patients could live, could be cured even though they had some residual cancer left behind. Then, what dawned on me is if this is happening in testicular cancer, it probably is happening in other solid tumors which also at that time most people didn’t appreciated, but almost all cancers arise in organs or tissues that have stem cell populations specific for that tissue. Since testicular cancer, we already had a drug that hit the stem cell population, I thought there’s no reason to really go after testicular cancer, but let’s look at another cancer and I decided on breast cancer because it was a major problem with unmet need.
I went to Max Wicha who was at Michigan and was kind of the cancer center then. He was taking care of breast cancer patients and I told Max and I said, “Max, I think breast cancer is a stem cell disease or has stem cells, but need to prove it and you are seeing patients. Can you get tumor material for me?” Max thought about it and said, “You know that could be a good idea” and started getting tumor samples to my lab and we did stem cell biology and we ask a very simple question. Could all the cells in the tumor, do they all have stem cell properties or was it only some of them?
To make a long story short and we studied at that time it was mostly estrogen-receptor positive tumors. In fact, the first study it was all estrogen-receptor positive tumors. What we found is in eight of the nine tumors we looked at, they indeed seem to have stem cell disease and that some of the cells could give rise to tumors and some of the cells didn’t. The cells that could give rise to tumors had all the characteristics of immature mammary epithelial cells and they could give rise to cancer cells. That’s basically how the discovery was made.
The reason I felt that was important is, again, going back to testicular cancer, if it’s a subset of cells that behave like stem cells, then you have to understand what those cells are and what makes them thick. In other words, what enables them to behave like stem cells in order to try to find drugs that will attack that population just like we have drugs in testicular cancer. That was the rather naïve reasoning behind that initial discovery and why I wanted to understand what’s going on and basically to understand what the self-renewal machinery. In other words, the machinery that stem cells used to make more stem cells in the cancer cells.
The other half of my lab studies self-renewal machinery and normal stem cells. At exactly the same time, the lab discovered the first gene that drives self-renewal of adult stem cells in multiple tissues. Again, the lab was already geared to study self-renewal and how stem cells drove an organ or in the case of cancer, abnormal growth, you can consider a tumor of an organ. Again, by understanding the similarities and differences between normal and cancer, I could probably give clues that would have therapeutic impact.
Chris Riback: It’s fascinating to me how connected the various areas of cancer research can be. I’ve heard this from other scientist as well and in your case you call it naïve. I don’t think others would agree, but it was having the insight and ability to connect what you are seeing in the testicular cancer world and thinking, “Wait a second. Where else can I apply this?” You chose breast cancer. What was that like for you when you were the first to identify breast cancer stem cells. I can’t imagine that after so many years what that moment is like.
Dr. Clarke: When you make a fundamental discovery and truly fundamental discoveries happen every five or six years for even the best people. When there’s a fundamental discovery that me and my lab makes, it’s elation and it’s more like you see something and when you first see it, you realized that no one else in the world knows this at this point in time. You realized the importance. You know when you make those discoveries. You know that when they are put out to the world, other people are going to work on them and they are going to be able to use those discoveries to build on them and go forward.
If you go back to my original statement why I did what I did, what really drives me in the end is I love fundamental discoveries. I was a really, really good chess player when I was a kid. I love playing chess. I love those kinds of intellectual games, but really what drives me in the end, I want to see these discoveries lead to benefit for people that suffer from the diseases I’m studying. It’s a combination of elation from making the discovery, but also realizing that this might be a piece in the puzzle that will improve people’s lives. In the end, if I can look back like Larry Einhorn and say that I’ve done some stuff that helps people, that’s ultimately what will make me happiest.
In a related disease, we just had a New England Journal paper on colon cancer stem cells. After we found breast cancer, we look in colon cancer for two reasons. One, we wanted to see is this a common model in epithelial tumors. The second is to try to understand if common mechanisms are being used by different cancers. Let me back up a little bit. In breast cancer, about 10 years ago now, we showed that measuring the number of stem cells on a tumor that the more stem cells that are in a tumor, the poor prognosis. That makes sense because the more cells that you have in a tumor that can drive metastasis and new tumors, the worse off you would expect someone to be. That was the hypothesis. It turned out to be true in breast cancer.
Flash forward, we are applying the same principles to colon cancer using advances and what we knew about stem cell populations and also bioinformatics approach somebody here at Stanford, Debashis Sahoo, who developed. Then, using markers for colon cancer that Piero Dalerba, who is now at Columbia discovered while he was in the lab. We were able to refine the ability to count stem cells more accurately in tumors and we were able to show in colon cancer that if you have about 5% of tumors were predominantly stem cells, had a very high cancer stem cell frequency. You would predict that those would be very, very bad actors even in early stage colon cancer. We found that indeed that was the case.
Then what we did is we said, “What happens if these very early stage colon cancer patients are not being treated with adjuvant therapy? What happens if they were treated with adjuvant therapy?” We found that lo and behold they actually benefited and there’s actually increase survival. Basically, what that shows is that by using the stem cell biology approach, we probably have changed treatment of a subgroup of patients with early stage colon cancer who actually are cured with adjuvant therapy. That’s the first example I know of stem cell biology actually being directly useful for clinical decisions to change therapy that save people’s lives.
Immediately when we saw that, we applied exactly the same tools to look at breast cancer. Preliminary data suggest we may have a gene that will do the same thing in breast cancer predict patients who are going to respond to therapy. We need to validate that. That’s one of the things we are planning on doing in the next couple of years is the preliminary data looks very, very promising, but we need to go in and validate that. I’m talking with other members of BCRF to get the material we need to see if what worked in colon cancer also works in breast cancer.
Chris Riback: Is that what’s key to making these fundamental discoveries that you mentioned, the ones that are really groundbreaking? By your math, if you do it all well and I assumed with a little bit of luck thrown in over long career, you may have five or six or seven fundamental discoveries. It’s incredible, but it’s not like there is one a year, they take time. You also seek to connect these ideas and discoveries whether it’s from an area that you’ve been working on or someone else and find ways to connect that research.
Dr. Clarke: Exactly.
Chris Riback: I know from other BCRF conversations that such an important part to making real breakthrough. Do I have that right as we think about finding preventions or actionable treatments, not just for breast cancer, but really any kind. Is that detective work taking what you might see or learn from one area of research and really considering how might this apply to what I’m working on next? Is that key for any researcher to understand? I’d imagine that’s not so easy to realize and not so easy to realize which ideas or which discoveries actually transfer and which don’t.
Dr. Clarke: Some people realize it and some people don’t. It’s like everything in life. I think some people understand this and other people don’t. Part of it is in the way we are trained as oncologist. There’s certainly things in the breast that are different in the colon. For example, how estrogen and progesterone works is much different in the breast obviously than in the colon. When you start looking at the nuts and bolts of the cancer, there’s much more that is shared than different in the breast. I think what I’m learning is there’s a lot of similarities. If I were to put a ref number on it, the similarities between breast and colon is probably in the order of 80%, but there are things that are fundamentally different. It’s important to understand what’s the same and what’s different, number one.
It’s especially important for me because with stem cell biology, if you are attacking a fundamental stem cell program and we’ve done this in breast for example. That same program is being used by critical normal stem cells, for example, the intestinal epithelium. If you can effectively eliminate the cancer cells by hitting some of these critical stem cells of neural pathways, but you also eliminate normal gut stem cells frequently. If you do that, the patient is dead in three to five days because their gut is gone. They are bleeding. They are vomiting blood. They are passing blood through their rectum. They’ve got all the bacteria in their gut. It is now in their bloodstream and they’ve got infections that you can’t control. It’s just ugly.
By studying these two different systems, I also study normal breast epithelium and normal colon epithelium. Right now, one of the more exciting things in the lab is we’ve got a stem cell program that the breast is using one component, but the colon is using a related gene, but not the same gene. When you knock out the breast gene, the gene that the breast stem cells were using including that looks like the cancer cells from our data. The subjct lives and so the toxicity is theoretically tolerable. If you knock out the gene that the colon is using, it’s lethal. If we can get a specific inhibitor to the breast gene, then we shouldn’t be killing the colon epithelium.
Again, there are similarities and they are both using the same pathway, but they are using different genes to activate the pathway. By understanding these really fine details, for me that’s the holy grail is figuring out things in the breast that aren’t going to eliminate the normal colon, the normal skin, brain stem cells, blood stem cells. The holy grail is finding something that does that. That’s the reason for studying the similarities and differences of these different tissues.
Chris Riback: In listening to you now and throughout this conversation, it occurs to me that I can completely hear the chess player in you that you mentioned earlier. I don’t think you’ve lost that gamesmanship. We hear about how great chess players, the masters are thinking not just one move ahead but multiple moves ahead. It seems to me that that’s what you’ve done from testicular cancer, to breast cancer, to colon, back to breast. It’s also clear that a recurring thing for you an area that you’ve come back to in your research is relapse. It’s driven so much of your previous work and it is central to your current work. Why is that? Is it just that that is where your research took you or is there something about that aspect of this terrible disease, the incredible challenge that anyone would surely feel after beating one round of cancer only to relapse into a second round?
Dr. Clarke: Because that’s what kills people and that’s the chess game I’m playing. As you said, the chess game I’m trying to play is to figure out what’s driving that and the hope is to find a way to intervene that eliminates relapse, but doesn’t get rid of the normal stem cells and kill someone. That’s what the chess game is. Clearly, stem cell programs are involved in many types of relapse. I’m not going to say all. That would be stupid for me to say that’s always the case because I’m sure they’ll be examples where it doesn’t. Clearly, to relapse and kill, you have to have the central property of a stem cell which, again, is self-renewal, regenerating itself, retaining its proliferation capacity. The holy grail is to perturb that process in cancer cells so those cells no longer relapse while you don’t do that in normal stem cells or at least critical normal stem cells.
The whole reason for concentrating on the relapse is that’s what kills people. The primary tumor in reality doesn’t really kill anybody or very, very few people. It’s rare nowadays with the early detection. You can eliminate local disease pretty well, but it’s the relapse which kills people. That’s why I’m interested in relapse and extraordinarily interested in the cells that resist our standard therapies, the therapies that people get for regular treatment. I just saw an article yesterday that women with estrogen-receptor positive patients who have been treated with adjuvant therapy – you know, anti-estrogens – are still relapsing 20 years later. I guarantee the reason they are relapsing is because the cells I study haven’t all been eliminated by definition.
Again, that’s why I’m so interested in why are these cells resistant to our therapies. It turns out that many of the ways that they are resistant to our standard therapy are actually programs used by normal stem cells to protect themselves from stressors. If you eliminate a normal stem cell, say you eat some toxic substances that’s toxic to your gut, if you eliminate all the stem cells, you die, period. That’s the end. Stem cells have actually generated mechanisms to protect themselves from toxins and also immune therapies are very popular right now, but a lot of these protective mechanisms against immune system are actually they don’t just pop up in cancers. They actually are used by normal stem cells to protect themselves from the immune system. A lot of the resistance we are seeing and again it’s not going to be all, but a lot of the initial resistance we are seeing when people aren’t cured. These are normal stem cell programs that the cells are using to protect themselves. The key is trying to understand those and figure out if we can intervene again in the cancer to overcome them.
Chris Riback: I assume like any chess master, applying the ability to think several steps ahead and several moves ahead and not just the immediate move. Dr. Michael Clarke is Professor of Medicine at Stanford University, the biggest professor in cancer biology and Associate Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. He has been a BCRF grantee since 2005 and really connecting so many areas of study across so many areas of cancer. Dr. Clarke, thank you so much for your time. I’m Chris Riback. This is BCRF Conversations. To learn more about Breast Cancer Research Foundation or to subscribe to our podcast, go to bcrfcure.org/podcasts.
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