June 21, 2018

Gina Columbus

Max Wicha, MD, shares insight on the intriguing research being conducted on breast cancer stem cells.

Max Wicha, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Researchers are in the midst of developing new methods to attack cancer stem cells, specifically in breast cancer, with the use of vaccine and epigenetic therapies, according to Max Wicha, MD.

“One of the exciting prospects in ‘cooking’ all of these things up in the future is that one can imagine a scenario in which women who have breast cancer treatment would get monitoring [with] a blood test,” Wicha said. “And, if any cancer cells were found, then rather than going back on hormone therapy, women would be administered some cancer vaccine and not have the cancer stem cells.”

In the laboratory, work also includes “waking up” the dormant state of cancer stem cells and utilizing immunotherapy to target these cells.

Wicha, who is the Madeline and Sidney Forbes Professor of Oncology, Founding Director Emeritus, University of Michigan Comprehensive Cancer Center, shared insight on the intriguing research being conducted on breast cancer stem cells during the 2018 OncLive State of the Science Summit™ on Breast cancer.^®

OncLive: What do we know thus far about breast cancer stem cells?

In an interview, Wicha outlined the evolution of this research and ongoing trials designed to take a deeper dive into targeting these cancer stem cells.Wicha: It is now becoming very clear that cancers are composed of very heterogeneous cell populations. We know that mutations drive carcinogenesis. However, what has also become clear is that cancers are organized in a fashion in which they have a differentiation pattern that was never found in normal tissues.

Cancers are actually driven by a small component of cells that actually turn into cancer stem cells. These stem cells have many characteristics of normal stem cells, but they show dysregulated growth and are responsible for a major component of treatment resistance, as well as the [reason for] cancer metastases.

Over the years, we have learned that many of the treatments that we use, such as chemotherapy and radiation, preferentially kill the bulks of the tumors. Whereas the cancer stem cells, which comprise only about 1% to 5% of breast cancer tumors, are much more resistant to these therapies. We think that is the reason why many of our therapies are able to shrink cancers down; however, the cancer shrinkage is not necessarily associated with increased patient survival. Based on this, our group and others are trying to develop new ways to attack cancer stem cells in the clinic.

At the University of Michigan, we have one of the largest programs in the country designed to investigate new drugs that may target a pathway that regulates these cancer stem cells. We currently have 9 clinical trials of drugs to target cancer stem cells. Our approach is to look at these drugs to see whether they are safe in early-phase clinical trials and attempt to combine them with drugs that can target the bulk of cell populations. Interestingly, the drugs already in clinic to treat breast cancer generally turn out to also target some of the cancer stem cells. That may account for why some of these agents work remarkably well—better than expected—compared with other kinds of drugs or even targeted agents.

One of them is trastuzumab (Herceptin)—the drug that has revolutionized cancer treatment by targeting 20% of breast cancers that overexpress HER2. Our lab shows that the reason that HER2 is so important in breast cancer is that, in those cancers where it’s overexpressed, it drives the cancer stem cells. Therefore, when we actually treat HER2-positive breast cancer with trastuzumab or other HER2-targeting drugs— we are actually affecting the cancer stem cells. That is why patients do much better with cancer stem cell-targeting agents.

Another example of this is the CDK4/6 inhibitors. These new drugs have been a major boom to the treatment of estrogen receptor (ER)-positive breast cancer when added to hormone therapies; they more than double the time to tumor progression. It was thought that when a cell gets signaling to the ER, it has to signal the cells to grow through these cyclin genes and then a CDK4/6 inhibitor inhibits the cell cycle.

However, that doesn’t really make sense because the tumors actually shrink down with these inhibitors; it is not just inhibiting the cell cycle. Now, we know that CDK4/6 inhibitors do actually affect the cancer stem cell, too. We think that this explains why they’re so effective; not only are they inhibiting the bulk of the tumor cells that express ER, but they are also having an inhibitory effect on the cancer stem cells.

Another important area is tumor dormancy, which means cancer stem cells can remain in a hibernating and dormant state, sometimes for many years. Recent studies published this year in the New England Journal of Medicine have summarized the natural history of ER-positive breast cancer. The study results showed that rather than having a risk period like in ER-negative breast cancer, which is during the first 5 years, there is a constant risk that keeps going out as far as 30 years.

Those characteristics indicate that a woman has a risk of 1% every year of getting recurrent breast cancer—even 30 years later, she still has a risk of 1% per year. We and others have found that many women with ER-positive breast cancer harbor dormant cancer cells that are in their bone marrow. There is a great deal of research trying to gure out what wakes up these dormant stem cells from their sleep, and how does the woman, who is 25 years out from breast cancer, all of a sudden recur.

There was a very interesting abstract presented at the 2018 San Antonio Breast Cancer Symposium. It showed that if you look at women with ER-positive breast cancer and...if they don’t have any cells in the circulation at year 5, and all of a sudden start getting cells that could be detected in the circulation, they then have a 20-fold increased risk of getting recurrent breast cancer in the next 2 years. This gives us hope that, in the future, we can develop new methods to pick up women who are at risk for this recurrence and being able to treat them.

We have developed new methods to isolate circulating cancer stem cells in patients’ blood. In the primary tumors— these stem cells, in the blood—as many as 30% to 50% of circulating cells are actually cancer. We hope to be able to develop these tests, so we can determine which women are at risk of recurring. The challenge will be what approach can we use to target these cells, and [can we] give them the same therapy as they had initially?

Finally, how does all of this relate to immunotherapy? One of the most exciting areas of cancer research has been the development of immune therapies, such as the immune checkpoint blockers. As many as 40% of patients with metastatic melanoma can benefit from these checkpoint inhibitors. Unfortunately, for the more common diseases, like breast cancer, they don’t work nearly as well. Even with triple-negative breast cancer, which is the most responsive of any checkpoint inhibitor, we’ve been trying to understand why the benefit is so low in breast cancer and other cancers.

One reason seems to be that these tumors are “cold” tumors, which mean tumors that don’t evoke an immune response to begin with. They don’t have immune lymphocytes in the tumor. We and others have been trying to develop vaccines that can immunize patients so that their immune system then can recognize the tumors and make the checkpoint inhibitors work much better.

How long has this type of research been underway? What are the challenges in getting these types of developments to the clinic?

We use 2 approaches. One [involves] developing a program to make cancer-specific vaccines, which will generate peptides that represent the mutations in cancers by immunizing patients against their own immune checkpoints. We are developing this protocol now. We are also working on ways of finding common antigens that are expressed in cancer stem cells, and whether we can make vaccines against the cancer stem cells. We are looking at antigens that are not expressed in adult stem cells; were looking at oncofetal antigens that are in cancer stem cells. It’s those antigens that are expressed only in the embryo and not in adult tissue; we are trying to see whether we can use these as immunogens to potentially develop vaccines against patient cancer stem cells.This was proposed many years ago, before we knew about stem cells. Our laboratory was actually the first to identify stem cells in breast cancer; that was the first in any solid cancer. It was in 2003. Since that time, what has happened is that the research in the basic science community, in the laboratories of cancer stem cells, has really flourished.

But, as the case with virtually everything in cancer research, clinical research lagged at least a decade behind what was going on in the laboratory. When you actually see this play out is when you look at some of the basic science meetings and compare it with the clinical meetings. It takes 5 to 10 years for stuff to move through to big clinical trials. It is matter of time delay in order to get these to the clinic. One of the key things will be the clinical trials [of drugs] targeting cancer stem cells that will have to prove their efficacy. Hopefully, that will happen over the next few years and then people will pay attention to this much more.

For the next decade [after discovering cancer stem cells in 2003], we went on using the same models, but what we didn’t realize at the time was that the immune system was not present in these mice, because we were using immune-suppressive mice. We missed a whole component that the immune system regulates cancer cells and stem cells and, in return, have unique ways that they evade the immune system. What we are finding is that we have to look at both the immune system and the cancer stem cell together as the unit and figure out how we can develop drugs that can target both of them.

One of the problems, when we first developed cancer stem cell-targeting drugs, we didn’t realize that some of the pathways being used by the cancer stem cells were also being used by the immune system to fight off the cancer—so some of them turned out to be immune suppressive. If you didn’t know that, it could become a big problem. Now that we do know that, it means that you have to develop new things, like the cancer vaccines against stem cells, so that we can harness the immune system to fight off the cancer stem cell than have the immune system stimulate the stem cell.

Can you highlight some of the characteristics of cancer stem cells?

In the lab, we showed that some of the immune suppressor cells, like myeloid-derived suppressor cells, are potent stimulators of the cancer stem cells. What happens is, in a tissue when you get tissue injury, these immune cells come in and then the suppressor cells come in and shut off the immune system—but they stimulate the stem cells and the tissue to repair them. We are finding that the same thing happens in cancer. We will see much more cancer stem cell research in the clinic, but it’s going to take careful clinical trials to prove this because ...we all know there is a big difference between treating mice and treating patients.Over the last 30 years, there has been so much excitement with all of the mutations that really drive cancer. Not only are there 200 different kinds of cancer, but even within those cancers, there are all different kinds of cancers and mutations. From that point of view, it seems like it gets more and more complex and then you become more hopeless. However, we think there is an overriding model or hypothesis about how all of these mutations actually work.

What people are finding are that the mutations that drive cancer actually reprogram cells back to a stem-like state, and the cancer stem cell is even more like an embryonic stem cell that is like a tissue stem cell sitting in this state.

Another reason that cancer has been so hard to cure is plasticity. This is the ability for cells to rapidly adapt to their environment and change their makeup and the pathways that drive them. What the history of targeted therapies has been is, if we can define the mutations in a tumor and decide then which drug might target that particular mutation or pathway...then the cancer becomes resistant. We initially thought that the way the cancer became resistant is they just mutated and got another mutation that made them resistant. However, it turns out that more than half the time they don’t mutate at all.

What happens is that the cancer just changes its form like a chameleon; it’s quiet in one pathway and you inhibit one pathway, it rewires the circuit and [the cancer] depends on a different pathway. The reason it does is because it’s the stem cell doing it. The stem cell is the most plastic cell that you have. If you inhibit one pathway, it chooses another.

Could you highlight a couple of ongoing clinical trials that explore this further?

That’s why you can’t cure cancer; you use a targeted therapy, one [pathway] knocks down and a cancer stem cell reprograms. Based on that knowledge, in some of our latest research we freeze the cancer stem cells so that it loses its plasticity and then we attack it so it can’t just change its form—that’s how we might be able to kill it. This is along with the vaccines. These epigenetic therapies freeze the cancer stem cells, so it loses its plasticity.All are early, phase I trials; they pick a different pathway, so a drug that targets the NOTCH1 pathway, the Wnt pathway, Hedgehog pathway, and immunotherapies that may be aimed at targeting cancer stem cells. We also have a protocol for HER2-positive breast cancer that is resistant to HER2 blockers by targeting the IL-6 receptor, which we know accounts for the resistance of the cancer stem cell in HER2-positive breast cancer. That is a trial that we just opened