Max Wicha, MD
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.
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.
OncLive: What do we know thus far about breast cancer stem cells?
: 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.