New Therapy Targets Chemo-Resistant Breast Cancer

Scientists say they have identified what triggers the most aggressive breast cancer cells to proliferate despite the killer effects of chemotherapy. And knowing the mechanism behind what allows these cancer cells to survive, they say, has led to new approaches that make chemotherapy deadly to them in mice trials.

Current cancer theory holds that cancer treatments are at times ineffective because while they kill off many cells, they are ineffective at killing the “stem cells” of cancer. Much like regular stem cells, these cells are self-renewing; resistant to medicines and therapies and able to restart tumor growth after chemotherapy. Unless these cancer stem cells are destroyed, they can regrow and spread malignant cells and spread to other parts of the body.

“Breast cancer stem cells pose a serious problem for therapy,” says lead study investigator Dr. Gregg Semenza, director of the Vascular Biology Program at the Johns Hopkins Institute for Cell Engineering and a member of the Johns Hopkins Kimmel Cancer Center. “These are the cells that can break away from a tumor and metastasize; these are the cells you most want to kill with chemotherapy. Paradoxically, though, cancer stem cells are quite resistant to chemotherapy.”

Semenza and researchers at Johns Hopkins say these cancer stem cells are most often found in the centers of tumors, where oxygen levels are low. They survive via proteins called hypoxia-inducible factors (HIFs), which turn on genes that help the cells survive in this low-oxygen environment.

In their research, published in Cell Reports, Semenza and his colleagues analyzed multiple human breast cancer cell lines grown in the lab. They exposed them to chemotherapy drugs, including carboplatin, which stops tumor growth by attacking cancer cell DNA. The team found that the cancer cells that survived had higher levels of a protein called glutathione-S-transferase O1, or GSTO1. Experiments showed that HIF proteins controlled the production of GSTO1 in breast cancer cells when they were exposed to chemotherapy; if HIF activity was blocked, GSTO1 was not produced.

In mice experiments, the loss of the protein GSTO1 decreased the number of cancer stem cells, thus preventing the spread of the cancer cells.

The study showed that blocking the GSTO1 protein may improve the effectiveness of chemotherapy. Semenza and his team are working to develop drugs that can block the HIFs, with the hope that HIF inhibitors will make chemotherapy much more effective.