Dr. Max S. Wicha Video (Text Version)
Title: Overcoming Resistance to Her-2 Targeted Therapies
Investigator: Max S. Wicha, M.D., University of Michigan Comprehensive Cancer Center
Our research concerns understanding why cancers become resistant to treatment and central to this is the concept that cancer stem cells, which are the roots that really drive cancers, are at the heart of why cancers become resistant. We now have new ways to overcome this resistance and attack the cancer stem cells. Hopefully, this will result in better outcomes for women with advanced breast cancer.
There are different forms of breast cancer and a particularly aggressive form of breast cancer is called HER-2 positive breast cancer. About 20 percent of women have too much expression of the HER-2 gene. One of the greatest advances in the treatment of breast cancer has been the development of HER-2 targeted therapies like Trastuzumab. However half of women who are treated with Trastuzumab who have advanced breast cancer don’t respond at all, and the ones that do respond most of them become resistant to Trastuzumab within about a year of treatment.
We made the discovery several years ago that the HER-2 gene was an important driver of a subpopulation of cells within breast cancers that we call cancer stem cells. These are the roots of the cancer that are actually driving the cancer. And so we knew that HER-2 was driving the cancer stem cells, the question is what happens when these cells become resistant to Herceptin therapy.
It’s been reported that over half of the women who become resistant to HER-2 treatment delete a gene called the PTEN gene, which is a tumor suppressor gene. And so we created a model in which we knocked down PTEN expression in breast cancer cell lines. We also overexpressed HER-2 so we now have cells here. These are MCF7 cells, the controlled tumors, tumors that we knocked down PTEN, tumors that we overexpress HER-2 or both, and you can see that they get progressively larger.
Importantly our lab has developed markers or protein markers of cancer stem cells so we can actually measure the cancer stem cells and measure the effect of these gene changes on the cancer stem cells. And what you can see is that when we knock down PTEN, when we overexpress HER-2 and even more when we do both we get more stem cells.
The question is why are these stem cells activated. Stem cells are regulated by inflammatory mediators called cytokines, so we went to see whether the knock down of PTEN and overexpression of HER-2 was associated with cytokine production in these more aggressive tumors. And what we looked at here then is the cytokine interleukin six and interleukin eight. And what you can see is that there is a step-wise increase in both interleukin six and interleukin eight when we knock down PTEN or overexpress HER-2.
Furthermore these tumors where we do this become much more aggressive. They not only grow faster; they actually metastasize. This is a luciferase assay so this shows how they metastasized to distant sites. This suggests that there is an inflammatory loop consisting of IL-6 that maintains the tumor stem cell compartment. We then wanted to see if we could block that inflammatory loop. It turns out that there is an antibody that’s actually been developed that inhibits the IL-6 loop by blocking the receptor for IL-6. This is actually a medication called Tocilizumab, which is actually in the clinic to treat rheumatoid arthritis because IL-6 is involved in joint destruction in rheumatoid arthritis so it’s an approved drug. And what you can see here is when we give these treatments early this is—these are control animals, these are ones that we just treat with chemotherapy. You could see it has virtually no effect.
When we block AKT signaling we reduce the tumor compartment but when we block IL-6 signaling in addition to AKT we get a much more robust blocking of tumor growth and not only tumor growth; we actually also decrease the cancer stem cell component within these tumors.
What this suggests is that when PTEN is deleted, one of the reasons that cancers become resistant to Trastuzumab treatment is they activate an inflammatory loop composed of IL-6. An antibody to IL-6 is able to block this pathway, and based on this we have plans in the future to launch a clinical trial that will combine an IL-6 receptor antibody with an AKT inhibitor to treat women with resistant HER-2 Trastuzumab-resistant breast cancer.
I really like the DoD Program because it is a different kind of grant. They are willing to fund things that are high-risk and high-reward.
When I first started the research in cancer stem cells, this was not only such a high-risk, nobody really believed it. As a matter of fact when we first submitted our initial papers we had trouble getting them published because people really didn't want to believe that all of the cells in a cancer weren't the same and that there were only a sub-fraction of cells that were really the seeds driving the cancer.
The DoD was willing to take a chance on this new concept because if it was true it would have great implications for how we diagnose and treat and prevent breast cancer. So they were willing to take a chance on this and I think now there are literally hundreds of labs that are working on cancer stem cells and it’s become a very hot area, although still controversial area in cancer research.