When Cancer Fights Back

Breast cancer can stay in remission for many years, thanks to effective drugs like tamoxifen. But sometimes breast cancer reappears. A new drug under study at UT Southwestern holds promise for people who are facing recurrent breast cancer. The drug might be able to step in when tamoxifen and other drugs like it stop working.

Here’s what happens. For about 80 percent of people with breast cancer, the cancer is estrogen-sensitive. That means the cancer needs estrogen – a hormone produced by the ovaries, fat, and skin – to grow. Doctors typically prescribe hormone therapies such as tamoxifen that deprive the cancer cells of estrogen. These medications work by attaching to a protein on the cancer cells that is called the estrogen receptor. With the medication blocking this protein, the estrogen can’t enable the cancer cells to grow, so the cells can’t use the estrogen to drive growth. “We know that the best way to target cancer cells is to get rid of the estrogen,” says Ganesh V. Raj, M.D., Ph.D., Co-Leader of the Experimental Therapeutics Scientific Program at UT Southwestern’s Simmons Comprehensive Cancer Center.

Breast cancer survivors can take drugs like tamoxifen for years – even decades – to stop the estrogen from connecting with the cancer cells. But eventually, in up to one-third of people, these cancers become resistant to the hormone therapy. Over time, the estrogen receptor in the cancer cells mutates and changes shape, and the medication no longer fits into the estrogen receptor. Estrogen can then slip into the receptor, once again fueling the cancer’s growth. When this change happens and cancer recurs, doctors try to fight it with other drugs or chemotherapy. But those treatments might not be effective or might trigger unpleasant and dangerous side effects. So for years, researchers have been looking for other ways to treat breast cancer that has become resistant to hormone therapy.

Taking a Different Approach

Cancer researchers at UT Southwestern have discovered a new, first-in-class drug that may be able to step in when tamoxifen and other hormone therapies fail. “It’s fundamentally different from other existing drugs,” explains Dr. Raj. “Its unique mechanism overcomes the limitations of current therapies. The way [this new drug] works is that it blocks the estrogen receptor in a different way.” When the estrogen binds to the estrogen receptor it starts a series of events that ultimately fuel the cancer’s growth. The new drug, called ERX-11, blocks the estrogen receptor even when bound to estrogen, from interacting with other molecules in this series of events. So even if the estrogen is able to take bind to the estrogen receptor, the cancer cells still can’t use it for fuel. They can’t multiply. This research grew out of studies of prostate cancer, which is fueled by androgens – a class of hormones that includes testosterone. Researchers were studying the androgen receptor, but they faced some challenges. “To better understand how our drugs were working, we switched to the estrogen receptor, since much more was known about it. That’s how we were able to get further ahead with this drug,” Dr. Raj says.

Positive Signs in the Lab

ERX-11 has been successfully tested in mice and in cancer cells in the laboratory with no signs of toxicity. Researchers hope to move into clinical trials next year. Dr. Raj points out that this drug also has the potential to treat other hormone-sensitive cancers, including endometrial and ovarian cancers. And, it’s a drug that would be more convenient for patients than other treatments, since they could take it by mouth, rather than IV.

Other UT Southwestern researchers who are participating in the research are Shihong Ma, Ph.D., Senior Research Associate; Rui Li, Ph.D., Senior Research Associate; Xihui Liu, M.D., Ph.D., Instructor in Urology; Shino Murakami, Graduate Student Researcher; Wan-Ru Lee, Ph.D., Research Scientist; Vijay Gonugunta, Ph.D., Research Scientist; and Douglas Strand, Ph.D., Assistant Professor in Urology.