In gene therapy for breast cancer, the target is metastasis

Breast cancer remains the leading cancer diagnosis in women and, overall, the second-leading cause of cancer-related deaths in the U.S. The American Cancer Society reports that the five-year survival rate for women whose breast cancers are diagnosed at an early stage ? when the cancer cells are still localized ? is 98 percent. But if the breast cancer has metastasized, that five-year survival rate drops dramatically.

Now, City of Hope researcher Carlotta Glackin, Ph.D., associate professor in the Department of Neurosciences, has developed a drug that demonstrates in laboratory tests the ability to switch off metastasis in breast cancer cells. The findings were presented today at the annual meeting of the American Association for Cancer Research in Washington, D.C.

The process of breast cancer cells metastasizing to other areas in the body is influenced by the Twist1 gene. Researchers are developing a gene therapy that turns off the gene.

Breast cancer stimulates metastasis by taking over a process known as epithelial-mesenchymal? transition. This process encourages cells to break apart from the tumor and travel through the body to new locations, usually another organ. To keep the epithelial-mesenchymal transition going, breast cancer cells turn on a gene known as Twist1 to produce high levels of Twist1 protein.

The research team focused on controlling Twist1 expression as a means to control metastasis of breast cancer cells. The Twist1 gene is considered a good target because it isn?t active in most normal, healthy situations. The research team wrote in the study abstract: ?Twist1 is also a desirable target because it is almost nonexistent in adult tissues and thus its silencing would have minimal side effects.?

To turn off the Twist1 gene, the researchers developed a gene therapy that uses short interfering RNA. Because one limitation of RNA-based gene therapies is the ability to deliver enough of the RNA into cells to make a significant change, the team attached the short-interfering RNA to molecules known as dendrimers to ensure sufficient delivery. They then tested the effects on two highly invasive breast cancer cell lines, with positive results.

Analysis of the cell lines revealed a 90 percent reduction in Twist1 activity ? which lasted at least four days ? after treatment with the gene therapy. Additional tests showed a ?significant decrease in the invasive nature of the breast cancer cells.?

The results from this study will be the foundation for further development and experiments, perhaps leading to human clinical trials in a few years. The dendrimer is also being investigated in other metastatic cancers.

The research team also included City of Hope graduate students James Finlay and Cai Roberts.

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Source: http://breakthroughs.cityofhope.org/gene-therapy-breast-cancer/4375/

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