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Gamma-secretase inhibitors targeted resistant stem cells
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San Antonio Breast Cancer Symposium
Gamma-secretase inhibitors destroyed chemotherapy-resistant “mammosphere-forming” breast cancer stem cells in both clinical and preclinical studies, according to Jenny Chang, MD, medical director of the Lester and Sue Smith Breast Center at Baylor College of Medicine, who presented new results at the CTCR-AACR San Antonio Breast Cancer Symposium.
“Mammosphere-forming” human breast cancer cells are cells that have been found to have stem cell properties and are resistant to conventional chemotherapy. These cancer cells can be identified because of their protein signature; they express high levels of CD44, a protein involved in migration, and low or undetectable levels of the cell adhesion protein CD24. Gene analysis of these cells showed that a number of pathways are activated, such as Notch, PI3K and Hedgehog, compared to non-cancerous cells.
Researchers first implanted human triple-negative breast cancer cells into two sets of mice. The mice were then treated with a gamma-secretase inhibitor. After isolating tumors in the mice, researchers found that mammosphere formation was impaired. Tumor volume was not affected.
Researchers then studied tumor biopsies taken before and during treatment of a patient with metastatic breast cancer enrolled in a complementary clinical trial of a gamma-secretase inhibitor conducted at Baylor.
“In animal clinical trials using gamma-secretase inhibitors, the tumor volume was not changed too much, but the proportion of cancer stem cells in the tumor decreased,” she said. “In the corresponding human clinical trial, the same effect is seen with gamma-secretase inhibitors on cancer stem cells. Tumor regression was observed only after several rounds of chemotherapy.”
Chang and colleagues found that mammosphere-forming efficiency declined after the first cycle of the agent combined with chemotherapy. The researchers speculate that the gamma-secretase inhibitor “chemo-sensitizes” a significant proportion of normally chemo-resistant stem cells. – by Jason Harris
For more information:
- Chang J. #48. Presented at: the 32nd Annual CTCR-AACR San Antonio Breast Cancer Symposium; Dec. 9-11, 2009; San Antonio, Texas.
If we can block the pathways from the mother cells, we think that will be a very effective approach and we’re just now becoming able to do that. If stem cells are unable to repopulate the tumor, the tumor shrinks over time. That’s what we’ve seen in leukemias, and now in breast cancer. If we target this rare population of cells with specific drugs that don’t attack the other population of cells, eventually the tumor will go away because we’re killing off the mother cells.
- C. Kent Osborne, MD
Director, Dan L. Duncan
Cancer Center and the Lester and Sue Smith Breast Center, Baylor College of
Medicine
