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Experimental Drug Targets Chemo-Resistant Breast Cancer Stem Cells

December 11, 2009

In animal and patient studies, an experimental drug eliminated chemotherapy-resistant breast cancer stem cells ““ the cells that remain after treatment that could potentially refuel tumor growth, said researchers from Baylor College of Medicine and The University of Michigan at Ann Arbor today at the CTRC-AACR San Antonio Breast Cancer Symposium.

“In previous studies, we have identified a genetic pathway ““ called the Notch pathway ““ as a top target for eliminating these tumor-initiating, breast cancer stem cells,” said Dr. Jenny Chang, medical director of the Lester and Sue Smith Breast Center at BCM and a lead investigator of the study. “Now, we have found a compound that inhibits activation of this pathway, reducing the number of tumor-initiating or cancer-causing cells that come from the original tumor.”

Cell-to-cell communication

The Notch pathway is involved in cell-to-cell communication and is responsible for determining the fate of a cell when it divides. Mutations in the pathway can result in cancer.

“These breast cancer stem cells are dependent upon the Notch pathway for survival,” said Chang. Shutting it off depletes the supplies of stem cells.

In the study, the researchers used a drug that that inhibits a compound called gamma-secretase and blocks the Notch pathway.

“This drug inhibits the cleavage of the Notch receptor (where cell information is received) and stalls activation of the pathway,” said Chang.

Reduction of tumor originating cells

After the approach was shown effective in studies of mice that grew human tumors, she and her colleagues tested the drug in women with advanced breast cancer.

Combining the gamma-secretase inhibitor with common chemotherapy drugs targets two populations of cells. The chemotherapy attacks the ordinary tumor cells and the experimental compound goes after the breast cancer stem cells (also called tumor-initiating cells).

In the human studies, the researchers evaluated the stem cells or tumor initiating cells in biopsies taken before and after treatment. In both human and animal studies, inhibition of the pathway reduced the population of these tumor-originating cells that would otherwise remain after chemotherapy.

Future plans

The next step in research is to take this into larger studies involving patients (Phase III clinical studies), Chang said.

“If what we believe is true, we would eventually start using this therapy earlier in treatment,” said Chang.

The use of mice that grow human tumors could in the future shorten the course of developing new anti-cancer drugs, said Chang.

Other researchers who participated in this study include Melissa Landis, Anne Pavlick, Lacey Dobrolecki, Amber Froehlich, Dr. Angel Rodriguez, Dr. Mothaffar Rimawi and Dr. Michael Lewis, all of BCM, and Dr. Max Wicha and Hasan Korkaya, of The University of Michigan at Ann Arbor.

This study was supported by funding from Merck & Co., Inc.

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