Anti-angiogenic agents and cancer stem cells

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Published: 13 Apr 2012
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Dr Max Wicha - University of Michigan, Ann Arbor, USA

Dr Max Wicha talks about the session he chaired at the AACR 2012 Annual Meeting on clinical implications of cancer stem cells and large number of trials underway examining these cells.


He also highlights two examples; the effects of anti-angiogenic agents on cancer stem cells and role of HER 2 in driving cancer stem cells in human breast cancer.

AACR 2012 Annual Meeting, March 31st - April 4th, Chicago


Anti-angiogenic agents and cancer stem cells


Dr Max Wicha – University of Michigan, Ann Arbor, USA

Well I think this definition has created a little bit of confusion in the field, but essentially we’re all talking about the same types of cells. These are cells within a tumour that have the ability to transfer the tumour to immunosuppressed mice, so they are the cells that initiate a tumour and maintain the tumour. Furthermore, there’s evidence that these same cells go through the circulation and are the same cells that initiate metastasis, that’s why we’re all talking about the same thing.


What are you presenting at AACR 2012?


I’m going to be chairing a session talking about clinical implications of cancer stem cells. It’s interesting, there are literally hundreds of abstracts at this meeting on cancer stem cells, so the field has certainly taken off and gained a lot of interest. I’m going to focus on the clinical implications of cancer stem cells and it’s a very important time to do this because trials designed to target these tumour-initiating or cancer stem cells are now being initiated. So it’s important to look at what are the implications of these cells as we move these into the clinic.


Two examples I want to talk about are the effects of anti-angiogenic agents on cancer stem cells and the role of HER2 in driving cancer stem cells in human breast cancers. Anti-angiogenic agents were an area that generated much excitement over the last decade; the idea first originated by Judah Folkman that if we could cut off the blood supply to tumours, we could prevent their growth. A number of anti-angiogenic agents then have entered the market and been approved and have entered many clinical trials. I think I can be fair to say that the results have generally been disappointing. Although anti-angiogenic agents generally, in many tumour types, can delay the time to tumour progression, they have not been found to prolong patient survival. As a matter of fact, in breast cancer bevacizumab was initially approved and then the approval was later withdrawn when the studies showed that patients weren’t living longer using this drug.


Work in our laboratory provides a potential explanation for this. What we found was that when these anti-angiogenic agents are given to mice with breast tumours, the tumours delay their growth but once they grow the tumour stem cells actually increase in their proportion. This is generated through the production of hypoxia in the tumour, so as the blood supply to the tumour is choked off, tumours generate zones of hypoxia and the cancer stem cells are stimulated through HIF-1 alpha, a factor that is stimulated by hypoxia. This explains why patients who are on these agents may actually not live longer, because they actually then have tumours that are enriched in cancer stem cells which can stimulate invasion and metastasis.


The good news is that gives us a clue as to how we can attack these cells and combine other anti-cancer stem cell agents with anti-angiogenic agents. Indeed, in our mouse models if we now use inhibitors of cancer stem cells, agents that can inhibit pathways such as Notch or Wnt, we can cause the tumours to shrink down without an increase in cancer stem cells. We think this is very exciting and we’re now talking to several pharmaceutical companies about testing this in the clinic, in other words combining an anti-angiogenic agent with an anti-stem cell agent.


We can actually show in our mouse tumours, exactly in the same zones that are hypoxic, there is an increase in the cancer stem cell populations.


Are there any clinical trials combining these two types of agents?


We’ve proposed that now and I will show some new data showing that inhibitors of the Notch pathway, called gamma secretase inhibitors, which have already been in the clinic, we’ve already conducted a phase I clinical trial with Merck showing that this is a safe agent to use and it can knock down the cancer stem cell populations. We now show in our pre-clinical mouse models that when we combine a gamma secretase inhibitor with an anti-angiogenic agent we get a beneficial effect and can knock down the cancer stem cells too.


The second area I’d like to discuss concerns the HER2 gene in human breast cancer. Development of HER2 targeting agents is probably the biggest advance in breast cancer therapy. Women with HER2 amplified breast cancers, which represent about 20% of all women with breast cancers, when they get a HER2 blocking agent such as trastuzumab have a 50% reduction in their recurrence rate and we think those women are actually cured. So it’s been a wonderful advance.


Now, why does this work so well? We discovered several years ago that HER2 is a very important regulator of breast cancer stem cells and we think that when trastuzumab is given in the adjuvant setting, it can knock out these cells, resulting in cures of women.


A surprising study was published two years ago in the New England Journal of Medicine by Dr Sum Pakatal (?) in which he retrospectively analysed data from a large clinical trial of the National Adjuvant Breast Group, the NSABP. What he reported was not only did women who have HER2 amplification benefit from adjuvant trastuzumab but the benefit seemed to extend to even women whose tumours were called HER2 negative – very perplexing. Based on this, a large clinical trial, B47, has been initiated to try to see whether adjuvant trastuzumab can work in women even without HER2 amplification. However, there is no biological explanation for why a HER2 blocking agent should work in tumours that supposedly do not express HER2. What we’ve discovered recently is that in luminal breast cancers, which is the most common type, the type that is associated with oestrogen and progesterone receptor expression, but which are HER2 negative by classical criteria, in fact these tumours are not HER2 negative but the HER2 is expressed selectively in the cancer stem cell populations. So they’re called HER2 negative because only 1-5% of the cells express HER2. What we can demonstrate in our pre-clinical models is that adjuvant trastuzumab can completely knock out the stem cells in these tumours, even though they are HER2 negative by classical criteria.


So we think this provides an important lesson - that we have to look at molecular markers, not only in the whole populations but in the cancer stem cells. If we can knock out cancer stem cells in the adjuvant setting, we’ll be able to cure more patients with cancer.


Are you proposing that the tumour will die if the stem cells are removed?


Exactly, especially in the adjuvant setting, that’s where stem cell therapies will have their greatest effect. This explains why, if you take women with advanced disease and treat with trastuzumab, women were only the stem cells express HER2, that is the luminal breast cancers, won’t shrink down because only 1-5% of the cells are the stem cells. But in the adjuvant setting the only cells that can form a metastasis from a micrometastasis are the cancer stem cells. Therefore, if you can knock out cancer stem cells in the adjuvant setting it will have the greatest effect.


HER2 drives the stem cell itself but it’s not amplified. When HER2 is amplified in a tumour then all of the cells in the tumour express HER2. The HER2 that’s expressed in the luminal stem cells is not over-expressed, it’s a normal level of expression so it’s not nearly as high as in the amplified tumours but the crucial fact is that is the crucial regulator of these stem cells in the luminal breast cancers. By the way, these stem cells do not express oestrogen or progesterone receptor, even though the tumour as a whole does, the stem cells are ER or PR negative and they’re driven by the HER2 pathway.