2013 San Antonio Breast Cancer Symposium (SABCS)
Moving breast cancer stem cell therapies to the clinic
Dr Max Wicha - University of Michigan, Ann Arbor, USA
This is a very exciting time; cancer stem cells were first described in human leukaemias and then, about ten years ago, we described the existence of cancer stem cells in human breast cancers. Since that time there has been a tremendous amount of basic research as to how to identify cancer stem cells and why they’re important in human cancers. The exciting thing is that now, based on these concepts, cancer stem cell therapies are moving into the clinic and this raises a number of important issues of what’s the best way to do this and to move these therapies forward.
Can these breast cancer stem cells be isolated and then grow?
We’ve described techniques for the isolation of these cells and how to identify them using specific markers. We’ve also developed assays that can be used both in the laboratory as well as in mouse models to identify these cells. What we’ve now found is that cancer stem cells actually can exist in different states and this is what has created some confusion in the field because these states of cancer stem cells actually express different markers and that is part of the reason that different investigators have identified these cells using different markers. But what we have found now is that these different states of cancer stem cells are really very important in mediating the behaviour of these cancer stem cells. Some of the cancer stem cells undergo what we call an epithelial mesenchymal transition, or EMT, and these stem cells are characterised by a very specific expression of markers that we first described, that is they express the protein CD44 but not CD24. These cancer stem cells are very invasive and these are the stem cells that get into the circulation. However, these stem cells are largely quiescent and so when they reach a metastatic site they have to revert to a more epithelial state. These stem cells are characterised by the expression of aldehyde dehydrogenase and this flip between the EMT and the MET stem cell, we think, are absolutely required for the stem cell to display metastasis. Now that we understand that we are developing assays to actually measure these cells, both in tumours and in circulating cells in the blood.
Is it this latent state which makes them resistant to chemotherapy?
Yes, as a matter of fact what we’re finding is that the EMT state of the stem cell is probably the one that’s the most resistant to our therapies because this is the state where the stem cells go into a dormant state. We think that this may account for micrometastases, for instance, in the bone marrow that are quiescent and can stay dormant, sometimes for fifteen or twenty years. Then the cancer stem cell flips back to the epithelial state and we’re trying to figure out why that occurs. Then they may become more sensitive to treatment but there’s a reservoir of these quiescent stem cells in the body that are very difficult to eradicate.
Where are we in clinical terms?
What we’ve found actually is that some of our most successful therapies already are probably this successful because they target cancer stem cells and the best example for that is the HER2 targeted therapies. Probably the biggest advance in breast cancer treatment over the last ten years, arguably, has been the development of HER2 targeted therapeutics. Many studies have been done and many presentations at this conference have shown the tremendous efficacy of HER2 targeted therapies. We know that women who have HER2 positive breast cancers who receive HER2 targeted therapies in the adjuvant setting in particular have about a 50% decrease in the recurrence rate of their cancers. What we’ve found is that HER2 is a potent regulator of cancer stem cells and that explains why these HER2 targeted therapies are so effective.
But what we’ve discovered over the last year or two is that there are breast cancers that are currently classified now as HER2 negative which in fact actually have HER2 but it’s selectively expressed in the stem cells. That’s why we think that these cancers which are characterised as HER2 negative still may benefit from adjuvant therapies of HER2 blockade. This is, of course, being now tested in a large national trial, NSABP B-47, for women with clinically HER2 negative breast cancers to see if a year of adjuvant trastuzumab will reduce the occurrence. We’ve now recreated that in our preclinical models and have shown that particularly in ER positive luminal breast cancers HER2 is selectively expressed in the stem cells. As a matter of fact, when these ER positive breast cancers metastasise to the bone there is a selective up-regulation of HER2 expression and cancer stem cells in the bone microenvironment and we think that these cells are particularly susceptible to HER2 blockade explaining the potential efficacy of adjuvant HER2 blockade, even in women whose tumours don’t express HER2 overexpression in all of their cells.
Interestingly, women who have HER2 protein expression in their bone marrow cells when we do fluorescence in situ hybridisation, these cells do not have amplified HER2 as determined by fluorescence in situ hybridisation. This calls into question the current dogma or the current accepted protocols that fluorescence in situ hybridisation is the gold standard for HER2 and whether HER2 blockade will be effective because what it suggests is that HER2 may be playing an important role in regulating breast cancer stem cells, even in the absence of HER2 amplification. This also fits both ours and published data showing that in HER2 negative breast cancers there are frequently HER2 expressing cells in the blood of patients and this explains why, because these are HER2 expressing cancer stem cells that express HER2 in the absence of gene amplification. So what these studies imply is that we have to rethink not only the HER2 story but perhaps rethink how we develop adjuvant therapies because the way adjuvant therapies have been developed is to take therapies that can shrink down cancers in advanced disease and merely administer them in the early or adjuvant setting. What our study suggests is that shrinkage of cancers in advanced disease really is a marker of bulk tumour populations whereas growth for micrometastases in the adjuvant setting is only being able to be accomplished by the cancer stem cells. If you have different pathways that are regulating the cancer stem cells from the bulk populations, such as HER2 in non-amplified breast cancer, the adjuvant treatment may be able to exploit that by targeting the stem cells and thereby preventing recurrence.
The HER2 is just part now of the story and there are now many other clinical trials that are being initiated by many companies to actually target cancer stem cells. At our cancer centre at the University of Michigan we have nine clinical trials now that are targeting various pathways that regulate cancer stem cells. One of the challenges of this field is how are we going to measure the effects of these therapies on cancer stem cells since, according to the cancer stem cell model, we can’t use tumour shrinkage or tumour regression as determined by the so-called RECIST criteria; we can’t use those as a measure of cancer stem cells. So our laboratory, as well as others, are working very hard to develop more robust assays for circulating cells that will be able to not only assess cancer stem cells in the circulation of patients but to do molecular analysis of these cells to determine whether our therapies are actually effectively targeting cancer stem cells as well as the pathways that regulate them.
