August 2016 VOL 7, NO 7

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Interview with the Innovators

Cancer Stem Cell Research: A New Frontier in the Fight Against Cancer

An Interview with Stanton L. Gerson, MD, Case Comprehensive Cancer Center, and Zev A. Wainberg, MD, University of California, Los Angeles

Gerson-WainbergIWTIIn recent years, we have heard that cancer is becoming a chronic condition with patients benefiting from personalized treatment strategies, including biomarker identification and related targeted therapies and immunotherapies. However, despite these advances, recurrence and metastasis remain significant challenges. Research in cancer stem cells has identified these cells as the possible cause of recurrence, metastasis, and, quite possibly, the cancer itself. Cancer stem cells are a small subset of the total cancer cell population, and while chemotherapy and radiation have been shown to affect the majority of tumor cells, the cancer stem cell appears to be highly resistant to these therapies, resulting in tumor recurrence and metastasis. It is thought that cancer stem cells have the capacity to self-renew and differentiate into cancer cells, have divergent signaling pathways, are resistant to traditional therapies, and contribute to tumor recurrence and metastasis. To further understand the evolving field of cancer stem cell research and its implication for oncology care, the publishers of Journal of Oncology Navigation & Survivorship met with 2 experts at the forefront of the research, Stanton L. Gerson, MD, Case Comprehensive Cancer Center, and Zev A. Wainberg, MD, University of California, Los Angeles. Funding for this program was provided by Boston Biomedical.

JONSThank you for speaking with us today. To begin, can you please provide a definition of cancer stem cells and explain how they differ from normal stem cells?

Dr Gerson Cancer is a heterogeneous problem; we have confirmed that primary tumors and metastases can be very different in nature. Scientists have realized that perhaps there is a unique cell that causes the recurrence of cancer. Or possibly a unique cell that causes cancer. With this premise in mind, we sought to identify characteristics of the cells within tumors, specifically looking for features that were rarely present, and why they took on special roles.

The characteristics of cancer stem cells are the following: they know how to grow, and they know how to rest. It’s a very special feature. Most of our cells differentiate, slough off, and die; for example, skin or bone marrow cells. But a cancer stem cell can rest, which means it can lie dormant for days, months, or years. It can also replicate itself and divide many times. And those cells can spread to different locations and grow there.

JONSIt would appear that cancer stem cells are important in tumor initiation and heterogeneity, as well as relapse and metastasis. How exactly does that process work?

Dr Gerson A cancer stem cell has abnormal genetic changes that characterize cancer. They hijack, if you will, some normal cell genetic changes that are present and active only in certain normal stem cell populations. Embryonic stem cells have a very careful sequence of genetic activities that the rest of our cells have lost. That ability is reactivated as a cancer stem cell starts to grow and divide. There are genes that are responsible for keeping differentiation away, for allowing the cell to go dormant and then reactivate.

For instance, in a colon or gastric area, we really understand the stem cell sequence as we go from the bottom of a crypt up to the differentiated cells. The cell at the bottom of the crypt is termed the colon stem cell. That cell can grow and divide and become dormant.

A genetic change may come about that causes the cell to grow exponentially and form a polyp and, ultimately, a tumor. Those cells retain this ability of being able to grow without differentiating, which is a feature of very early stem cell populations.

Then, as a tumor enlarges, going from microscopic to a palpable lump, rare cells retain the stem cell capability inside the tumor. We may be able to eradicate 99% of a tumor, but that cancer stem cell survives. This is our challenge.

JONS What you’re saying is that cancer stem cells can migrate and regrow a tumor in a distant site from the primary. Does this also involve modification of the tumor microenvironment?

Dr Wainberg There’s a suggestion in the literature that the metastatic process, which occurs by a number of different genetic regulations, including things like epithelial-mesenchymal transition (EMT), may, in fact, be particularly more important in the cancer stem cell than in the rest of the tumor. There may be some specific attributes of the cancer stem cell that make them particularly inclined to have either an enhanced EMT process or other predilections to make the metastatic process more pronounced.

Dr Gerson That’s exactly right. Normally, cells are restricted to certain environments in which to grow. Meaning, you won’t find a liver cell in a lung. However, a tumor cell has lost that restriction capability. It has added to itself on its surface or its metabolism the capability to grow in different environments and influence that new environment. When the cell finds itself in a new environment, it can become dormant and wait for the environment to transform, or the cell can adapt via the EMT process, allowing the cell to thrive in its new environment.

The cell can feed on certain surface markers and growth factors that allow it to grow in this new environment and respond to the vasculature. In fact, the cell can encourage the vasculature to grow to create a blood supply. As it grows and divides, it has the nutrients that it needs and, ultimately, takes over the microenvironment.

It hijacks normal processes. There’s a process called TGF beta that controls a cell’s ability to grow, divide, and differentiate. It is thought to be a tumor suppressor. Yet in other settings it can cause EMT transformation. Then a cell of the tumor stem cell variety can grow and divide and form a much larger tumor.

JONS Despite the advances in chemotherapy and use of targeted agents and radiation therapy, the prognosis for patients with advanced cancers remains relatively poor. Drug resistance, metastasis, and recurrence even after extended periods of remission pose significant challenges to cancer management. How are cancer cells involved in promoting resistance to chemotherapy and radiation therapy?

Dr Wainberg With respect to the efficacy of cytotoxic chemotherapy, which is the principal way in which we treat cancer, we know that in a large number of cancers, the large majority of cytotoxics are effective. They temporarily can kill the bulk population of the tumor cell and bring down the degree of tumor burden for most patients. However, remaining cells can acquire new mutations or undergo epigenetic modifications that subsequently make them resistant to therapy.

Some of that process is probably driven by the inability of the cytotoxic chemotherapy or the radiation therapy to get to the cancer stem cells. Our challenge is to figure out how to get at both of these cellular populations.

With respect to resistance, there’s been a good amount of research and suggestion that classical chemotherapy in the majority of cancers can, in fact, induce some degree of resistance and perhaps even promotion of the cancer stem cell population.

Dr Gerson Current treatments can get rid of proliferating cells, cells that have lost the ability to stop their growth pattern or repair their DNA, and cells that aren’t close to vasculature. Then you’re left with cells that are a most resistant variety.

We’ve done some studies in lung cancer in which we try to identify cells that have the biologic characteristics of cancer stem cells by the surface marker characteristics. We enriched by 20-fold the cells that have the appearance of a cancer stem cell population. We can transplant them into mice much more frequently now.

Our research reflects the polymorphic nature of cancer stem cells, making it difficult to identify them. We think that they have some common characteristics, but they understand how to withstand DNA damage, and rest, and repair. They understand how to survive and grow with minimal nutrients, and they are very good at using glucose. They are capable of surviving as a single cell, rather than as a bulk. Those are some of the specific issues that therapeutics are attempting to address. And it’s a conversation that major medical centers are undertaking now.

JONS We’ve heard the term “stemness pathways”; can you define this term and discuss the mechanism for this process?

Dr Gerson The stemness features are the ability to self-renew, rest, grow when needed, and to spread and differentiate. Stemness also includes the ability to respond to external stimuli. They’re also able to stop a differentiation pattern.

The other feature that is interesting is that as cells differentiate, they lose many features of stemness, whereas in a cancer stem cell population, even in a heterogeneous tumor, we can identify cells that have retained stem properties that allow them to be resistant to both differentiation and conventional therapeutics.

Dr Wainberg The advantage to cells retaining stemness characteristics is that we can start to understand the signals that identify them as a stem cell, and then we can specifically target them.

Dr Gerson We want to understand how to target the bulk population of the tumor, and the much more complex situation of the stem cell.

JONS What molecular biomarkers are associated with cancer stem cells within a tumor?

Dr GersonThere are 2 approaches in identifying cancer stem cells. The first is to look for phenotypes. The other is to try a purification strategy in which we might look at the surface marker CD133, for instance, or the overexpression of aldehyde dehydrogenase, which we know is important for stem cell populations.

An interesting question is if those markers will be the right targets for a cancer stem cell therapeutic. That’s something that we’re working on actively.

Dr Wainberg I think there will be several biomarkers that define either a colon cancer stem cell or a gastric cancer stem cell or a lung cancer stem cell. It’s not 1 single surface biomarker. It’s probably a constellation of several.

JONS What are the treatment approaches to eradicate cancer stem cells within a tumor?

Dr Wainberg We’re just in the beginning of this field. We’re trying to understand from a therapeutic perspective if there is a mechanism to attack some of the cancer stem cell properties that make those cells unique.

There are a number of pathways that are potentially involved in stemness and in defining a cancer stem cell, whether it’s a canonical Wnt pathway, Hedgehog pathway, Notch pathway, or other pathways. Some of the efforts in this field involve therapeutics, both monoclonal antibodies and attacking the kinase domains directly if it’s relevant in those different pathways.

JONS Would these therapies be sequentially or concurrently aligned with conventional therapy?

Dr Wainberg At this point, the best strategy is to use them in combination until we have a better understanding of their optimal use. The strategy that many academic investigators have employed is to look at these drugs as partners in combination with either existing cytotoxic chemotherapies or other targeted therapies in a way to simultaneously get at the bulk tumor population and the cancer stem cells.

Doing clinical trials and clinical drug development for this group of molecules is a challenge because, on the one hand, we have patients with these malignancies who can benefit from these drugs, yet we’re not able to define the precise role of that individual cancer stem cell. The optimum strategy here is to try to combine these and see if we can get to some better understanding of both the science of blocking those pathways and, of course, achieving better durable remissions.

JONS As you start to develop randomized clinical trials that involve anticancer stem cell therapy, are there other different clinical end points that you need to incorporate?

Dr Wainberg We really are in the early phases of this evolving field, so our first step has been to identify pathways that may make cancer stem cells unique. Now, drugs are being developed to block these pathways. The next critical step is to ensure that these drugs are actually doing what we have proposed, that they’re actually blocking these pathways. Once that is demonstrated, we attempt to find pharmacodynamic markers, and then we start to think about randomized clinical trials. There’s hope and promise that randomized clinical trials are going to be done in the next few years that will answer the question of the importance of these pathways.

The randomized clinical trial designs are usually designed to add new investigational agents to the existing standard of care for a particular setting. Those trials are just starting out in this field.

Dr Gerson There are many end points. In cancer stem cell research, the question often relates to metastasis. Can we actually prevent the recurrence at the new site? That’s a much more difficult trial design and will take longer to answer. It may become the most important question at the end of the day. Can we prevent recurrence? Can we prevent a new metastatic site? There are situations where we would be delighted if we prevented metastasis regardless of what happens at the primary site.

JONS What preclinical data exist that are important for the anticancer stem cell approach to therapy?

Dr Gerson There are surprisingly good data of the STAT3 and Wnt pathways and the sonic Hedgehog pathways, where agents can block recurrence of disease, and, more importantly, block metastasis in a variety of model systems.

The synergy studies that have been done in mouse model systems have been quite impacting. The question is how to translate that into the proper clinical setting.

JONS At the 2015 ASCO meeting, the results from some very early-phase clinical studies with BBI608, also known as napabucasin, which is an orally administered investigational agent designed to inhibit cancer stem cell pathways by targeting STAT3, were presented. Can you provide your perspectives on those data?

Dr Wainberg This is one of these early studies that exemplifies what we’ve been speaking about—the potential in targeting a pathway that may be much more relevant in cancer stem cells than in the normal bulk tumor population. In this trial, the standard of care was paclitaxel, which is one of the standard treatments for metastatic gastric cancer. There were clinical responses to the combination of paclitaxel and BBI608, some of which were reasonably durable. This is a malignancy, unfortunately, that has a very poor prognosis. The fact that you could demonstrate some clinical responses as measured by classical clinical criteria is encouraging and warrants further exploration.

Dr GersonIt’s important to note that we’re looking at individuals with advanced disease. We’d like very much for a cancer stem cell therapeutic to be given early, not late. That’s a conundrum in medical oncology—our newest, potentially most powerful drugs are given to people at a late stage, when we’d really like to give them early on.

An important aspect of the study is that the combination was tolerated well; it didn’t make paclitaxel more toxic to patients. That allows us to think about the possibility of introducing this far earlier, perhaps either concurrent with therapy or at the end of the first course of therapy.

JONS Can you discuss some of the other molecular signaling pathways besides STAT3 that could be used as a focus for cancer stem cell therapy?

Dr Wainberg This is also a field still in its infancy, I would say, in some respects compared with other classical targeted therapeutics. In our lab, we’re running a clinical trial that is entirely distinct from the STAT3 pathway; it’s focused on the Hippo pathway, another potentially relevant pathway in cancer stem cell research. There are many other pathways under investigation as well.

Dr Gerson There’s an interesting question in the field of whether to target the surface of a cell that receives signals from the outside that tell the cell to grow. If you block a single protein at the signal pathway at the surface, you may not touch what’s going on within the nucleus. At the end of the day, we may very well be looking at the need to selectively combine 2 or 3 of these agents to really combat the ability of that cancer stem cell to grow.

JONS You mentioned that in the early clinical trials presented at ASCO, the drugs were well tolerated. Now, you’re talking about combination therapy. Is there a worry about toxicity? Is there a worry about impact on normal stem cells?

Dr Gerson As a stem cell biologist, the issue of affecting normal stem cells is less of a concern than commonly thought. Our normal stem cell populations are resilient. We know what to look for, in terms of side effects, that would lead us to worry about impacting normal stem cells. I’m frankly not concerned.

JONS It seems like most of the early clinical trials of anticancer stem cell therapy have been in either gastric or colorectal cancer. Are there other kinds of cancers? Are there hematologic malignancies that might be amenable to this approach?

Dr Gerson We’ve tried for a number of years with lymphoid and myeloid leukemia, as well as with myeloma. There are some intriguing data that suggest that we may be able to use the STAT3 inhibitor on a myeloma pathway. It is possible that the issue of a stem cell population in myeloma is most important in those individuals who have a refractory disease. Clinically, we know that we can remove 99% of myeloma, and yet patients are left with a small clone of cells that are incredibly resistant. That’s the ideal setting for this research.

It is more difficult in the setting of acute myeloid leukemia, where we’re up against going through a stem cell transplant, whether we’ll be able to come up with therapeutics. Furthermore, we’ve identified that there are these preleukemic stem cell clones.

You’ll see therapeutics coming up now with a better molecular characterization for the myeloid leukemias. In solid tumors, it’s a much more complex setting.

JONS What do you foresee as the future of cancer stem cell–targeted therapy over the next several years?

Dr Wainberg From the solid tumor perspective, we’re still learning what the cancer stem cell is, what drives it, what makes it unique, and its related phenotypic properties. Considering hematologic malignancies, as Dr Gerson alluded to, there’s perhaps a better definition of what those cells are, and, therefore, an easier way to target them.

In the solid tumors, it is more difficult to identify the correct cellular populations and, therefore, more difficult to determine if the drugs are getting to the appropriate target.

There have been a number of clinical trials already, some of which have failed in the clinic because they were either not able to demonstrate sufficient safety that would justify moving forward into clinical development, or in combination, we’re just not able to show the therapeutic advantages that were prespecified when the trials were designed.

As we design these clinical trials, the ideal circumstance is to identify the patient population that will receive the most benefit. In studying that specific patient population with a specific target, the end points are a little bit easier to attain.

In a solid tumor stem cell population, these combinations are still empiric. That’s going to change as we move forward and understand which stem cell properties drive which cancers.

Dr Gerson That was very well said. I would simply add that we’re going to be asking a set of questions as the data get better, our expectations will get greater. The first set simply addresses tolerance. The second will ask if we can improve partial responses and make them more durable. The third will ask if we can delay recurrence. Ultimately, we’re going to ask the question of how to handle the issue of dormancy.

A woman who has had a mastectomy or treatment for early-stage breast cancer that recurs 6 or 7 years later, what can we do about that? That might mean a long-term duration therapy to reduce the chances of that dormant cell ever coming back as a clinically manifested disease.

Dr Wainberg Some of my colleagues have suggested that this research is not that different from where immunotherapy was, maybe 30 years ago. There is a surge of research related to immunotherapy right now, with new drugs that are being driven by specific phenotypes.

JONS What should the practicing clinical oncologist know today about cancer stem cells?

Dr Gerson For the practicing oncologist, cancer stem cells are something they experience every day in their practice. That is, “What do I tell my patient is the cause for their recurrence 3 or 4 years after their primary resection or treatment?” In the myeloid leukemias, “Why are there preleukemic cells that we can’t manage?”

In myeloma, it’s “Why can’t I get rid of that last little bit of myeloma after the initial treatment has been so successful?” For the lung cancer patient, it’s “Why is it so hard to get that primary tumor to disappear completely after intensive therapy, chemotherapy, radiation therapy, and surgery?”

Six months, a year, 2 years after their initial treatment, “Why do they get a brain metastasis?” Our clinical oncologists are experiencing the cancer stem cell problem every day in their practice.

Dr Wainberg That’s exactly right. As a clinical oncologist, I see patients who relapse years after having been in remission with some of these cancers. It is probably the cancer stem cell that was never completely destroyed.

JONS Gentlemen, thank you for taking the time to speak with us today, and best of luck in this undertaking. We hope very much this research leads to a way to eradicate cancer stem cells.

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