Breast cancer stem cells are a new target for researchers as they look for better ways to treat breast cancer. Breast cancer stem cells are sometimes called "mother" cells of a breast cancer -- they make other breast cancer stem cells and regular breast cancer cells. Breast cancer stem cells make up about 1% of all cells in a breast cancer tumor.
Research has shown that current treatments effectively destroy regular cancer cells but are not good at destroying breast cancer stem cells. Because the breast cancer stem cells survive treatment, they can still create new regular breast cancer cells to replace the ones that have been destroyed. Researchers think breast cancer stem cells' ability to survive treatment is a big part of the reason why breast cancer can come back (recur), fail to respond to treatment, or become resistant to treatment.
The very preliminary study reviewed here found that gamma secretase inhibitors, a new type of targeted therapy medicine, may weaken or destroy breast cancer stem cells. These results were presented at the 2009 San Antonio Breast Cancer Symposium.
Gamma secretase inhibitors also are known as Notch inhibitors. The Notch pathway is the mechanism that controls the number and activity of breast cancer stem cells. Researchers want to know if using Notch inhibitors in combination with traditional breast cancer treatments can improve the overall response to treatment.
In one study, researchers implanted tumor tissue containing breast cancer stem cells and regular breast cancer cells into mice. The mice then were treated with either a Notch inhibitor called MRK-003 or a placebo (sugar pill). The results suggested the Notch inhibitor weakened or destroyed the breast cancer stem cells.
New regular breast cancer cells produced by breast cancer stem cells cluster together in what's called a mammosphere. The mice treated with MRK-003 had a lower number of mammospheres compared to mice that got the placebo. Eventually the implanted tumor got smaller in mice that got MRK-003.
Because these results were promising, the researchers tested another experimental Notch inhibitor, MK-0752, in 35 women diagnosed with advanced-stage breast cancer who were being treated with Taxotere (chemical name: docetaxel). Before treatment, each cancer was biopsied and analyzed to count the number of breast cancer stem cells and mammospheres. When treatment with MK-0752 and Taxotere was completed, the cancers were biopsied and analyzed again. The researchers found that the number of breast cancer stem cells and mammospheres were considerably lower. These results suggest that the Notch inhibitor weakened or destroyed the breast cancer stem cells.
These results sound promising, but research on Notch inhibitors is just getting started. More work will help doctors figure out if Notch inhibitors could effectively and safely treat breast cancer. Research suggests that using a Notch inhibitor early on in treatment could improve overall treatment response by weakening or destroying breast cancer stem cells.
Stay tuned to Breastcancer.org for the latest news on research that can lead to new and better ways to treat breast cancer.
SAN ANTONIO (MedPage Today) -- Targeting breast cancer stem cells with experimental "Notch" inhibitors appears promising in the fight against recurrence, researchers said here.
The novel agents, also known as gamma secretase inhibitors, reduced the number of cancer tumor cells, although with little immediate impact on tumor volume, Jenny Chang, MD, of Baylor College of Medicine in Houston, and colleagues found.
Their early phase experiments in mice and a small group of patients suggested a "paradigm shift" in looking at breast cancer treatment, Chang reported at the San Antonio Breast Cancer Symposium.
Conventional therapy largely aims at volume -- shrink and remove the tumor and keep the mass from regrowing, noted William Gradishar, MD, of the Lurie Cancer Center at Northwestern University in Chicago, who moderated a press conference at which the study was discussed.
But the roughly 1% of tumor cells dubbed "mother cells" that produce new stem cells and regular tumor "daughter" cells, typically survive chemotherapy, endocrine therapy, and radiation.
"The current available therapies really aren't affecting that population of cells," Gradishar added.
In fact, one prior study from Chang's group showed that the cancer stem cells actually more than tripled during neoadjuvant chemotherapy.
"The cancer stem cell hypothesis is that you need to kill both populations -- the bulk of the tumor as well as the cancer stem cells -- and they're regulated by different mechanisms," Chang said.
To find out what was driving these hardy cells, the researchers did a gene expression analysis, which revealed Notch signaling as the top candidate.
The Notch pathway is involved in normal mammary development, in communication between cells, and in determining what happens to a cell when it divides, thus "regulating the self-renewal of cancer stem cells," Chang said in an interview with MedPage Today.
She and her team implanted mice with human breast cancer biopsy material that included breast cancer stem cells, then gave them a Notch inhibitor (MRK-003) or a placebo.
MRK-003 significantly reduced formation of clusters of tumor cells called mammospheres compared with placebo.
Tumor volume dropped about fourfold over 21 days with the agent compared with about a threefold decrease with placebo or docetaxel alone or in combination with the Notch inhibitor, but the difference between groups was not significant, likely due to the short duration, Chang said.
With this evidence in hand, Chang's group started a Phase Ib/II clinical trial with another Notch inhibitor (MK-0752) -- 35 women were given the Notch inhibitor before each docetaxel administration for six cycles.
Compared with baseline biopsies, those taken at the end of treatment had significantly fewer cancer stem cells measured by CD44/CD24 expression. The formation of mammosphere cell clusters fell significantly as well.
Again, though, tumor regression wasn't seen immediately with Notch inhibition. It occurred only after several rounds of therapy.
This likely reflects daughter cells dying off from chemotherapy with progressively fewer stem cells to repopulate them, Chang said.
Given the proposed mechanism, Notch inhibitors are likely to be developed for upfront use in combination with agents to "debulk" the daughter cells or for chronic administration in the adjuvant setting to prevent recurrence, she speculated.
Her group plans a larger Phase II trial, while others are developing agents targeting other cancer stem cell pathways, such as Hedgehog.
"Trying to identify what really makes them grow, to interfere with those pathways may ultimately lead to better outcomes for patients with both early and advanced stage disease," Gradishar said.
The study was funded by Merck, which is developing the gama secretase inhibitor used.
Chang made no disclosures other than the funding for the study.
Gradishar reported being a consultant for Bayer and Nexavar.
Primary source: San Antonio Breast Cancer Symposium Source reference: Chang J, et al "Targeting intrinsically-resistant breast cancer stem cells with gamma-secretase inhibitors " SABCS 2009; Abstract 48.
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