SABCS congress news: Promising results from 'Notch' pathway inhibitor tests

11 Dec 2009

Treating breast cancer with a "Notch pathway inhibitor reduced the ability of cancer stem cells to replenish themselves and promote tumor growth, researchers reported at the annual CTRC-AACR San Antonio Breast Cancer Symposium, USA. These findings suggest that ongoing clinical trials testing this class of agents could offer promising results, especially when combined with other anticancer treatments.

"The Notch pathway regulates self-renewal of stem cells and our research indicates that it also regulates cancer stem cell self-renewal," said the study's lead author, Jenny Chang, M.D., professor of medicine at Baylor College of Medicine.

The impact of using a Notch inhibitor, she said, was to sensitise a significant proportion of otherwise treatment-resistant cancer stem cells, and this supports the notion that a select subpopulation of cells in breast cancer is largely responsible for disease recurrence and cancer spread.

Researchers from Baylor College of Medicine, University of Michigan and Dana-Farber Cancer Institute focused on "mammosphere-forming" human breast cancer cells - 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.

In this study, researchers tested gamma-secretase inhibitors in preclinical cancer stem cell models and a complementary clinical trial of a gamma-secretase inhibitor in breast cancer patients. Gamma-secretase is required for activation of the Notch signaling pathway, which regulates self-renewal of stem cells.

The research team implanted human triple-negative breast cancer obtained from patients in two independent sets of mice, and then treated them with a gamma-secretase inhibitor. They isolated the tumors in the mice and found that mammosphere formation was impaired, but tumor volume was not affected.

"Because the cancer stem cell population may be a very small percentage of the tumour cells (0.1 percent to 1 percent), tumour volume measurement is not sensitive enough to measure effects on the cancer stem cell population," Chang said.

Researchers then studied tumor biopsies taken from a patient with metastatic breast cancer enrolled in a complementary clinical trial of a gamma-secretase inhibitor conducted at Baylor College of Medicine. They looked at biopsies before and during treatment. Findings showed that mammosphere-forming efficiency declined after the first cycle of the agent combined with chemotherapy, and tumor response was seen only after several rounds of therapy.

"The agent reduced the tumorigenic cancer cells," Chang said. "To eliminate these cells, combination therapy that targets additional pathways regulating cancer stem cells will be essential."


Watch an interview with Prof Jenny Chang on ecancertv here.