Looking for New Ways to Tackle Toughest-to-Treat Breast Cancer

Early-stage research suggests there may be a new way to attack the toughest-to-treat breast cancer – triple negative.

Triple negative breast cancer cells have three issues that make treatment options slim. They lack two proteins – estrogen receptor and progesterone receptor – for which there are useful treatments, called hormone therapy drugs. The other problem is related to another protein, called HER2/neu. If breast cancer cells have too much HER2, they could be treated with a drug that specifically targets that problem. But triple negative breast cancer cells do not have too much HER2, so that therapy option is off the table.

That leaves chemotherapy as the primary means of treating patients with triple negative breast cancer. Triple negative breast cancers, though, are highly resistant to chemotherapy. Less than 20% of women with triple negative breast cancer who are treated with chemo drugs see lasting results, known as a durable response.

Chemo May Have an Unexpected Effect

Researchers are just starting to figure out why triple negative breast cancers are so resistant to chemotherapy. One possible reason for this: Chemo drugs may actually be fueling some breast cancer cells. This is according to an early-stage study by researchers at Johns Hopkins Medicine, published online December 1, 2014 in the journal Proceedings of the National Academy of Sciences.

The research team determined that the chemotherapy drugs paclitaxel and gemcitabine cause a molecule called Hypoxia-inducible factor 1 (HIF1) to snap into action, which in turn starts a process that ultimately produces more breast cancer stem cells. Such cells are believed to be the only breast cancer cells in the tumor that can cause the cancer to spread to other parts of the body or to recur.

“So these are the cells that really need to be killed by therapy and yet are the ones most resistant to it,” says Gregg Semenza, MD, Ph.D, a researcher who worked on the Johns Hopkins study. The work was funded in part by a prestigious American Cancer Society Research Professor grant, which Semenza was initially awarded in 2012.

Dr. Sememza and Debangshu Samanta in Johns Hopkins lab

Experiments in Mice Suggest Combination Treatment May Be Better

Semenza sees drugs that target HIF1 as a potential strategy for making chemotherapy more effective and helping more triple negative breast cancer patients survive. “HIF1 is a master regulator; it controls the expression of many genes, so when you inhibit it, you can have a really big effect,” says Semenza.

In his experiments in mice, Semenza tested treating triple negative breast cancer with just chemotherapy and with a chemo-HIF1 combination therapy. “If treated with chemo alone, we could decrease tumor growth, but it would grow again when we stopped the chemo; but if treated with a HIF1 inhibitor and chemo, we could pretty much eradicate the tumors in mice.

“These experiments suggest that blocking HIF1 might allow chemo to be more effective in the treatment of breast cancer,” Semenza says.

Existing Drugs Could Solve the Triple Negative Chemo Problem

Semenza says there are several drugs already being tested in clinical trials that block HIF1. If they prove safe and effective, the next step would be to start a trial to test a chemo-HIF1 combination therapy in triple negative breast cancer patients.

Semenza’s study adds to the growing research aiming to overcome the challenges of treating triple negative breast cancer. He said that a study published by Vanderbilt researchers a couple years ago showed that a different molecule acted in a similar manner to HIF1 in reaction to chemotherapy. And, if targeted, it could also help block the effects of chemo drugs on cancer stem cells.

“Either one of these pathways could be targeted for therapy; there may be several different strategies that could be brought to bear,” says Semenza. The bottom line according to Semenza is that “there is a great need to improve treatment for triple negative breast cancer patients.”

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