Disruptive double agent

BUFFALO, N.Y.—In a lab focusing on estrogen receptors and breast cancers, researchers at Roswell Park Comprehensive Cancer Center, a National Cancer Institute-designated center seeking personalized approaches to cancer, found that a widely used cancer drug may have a new role that could change the way an aggressive form of cancer is treated. The article describing the research appeared in the Journal of the National Cancer Institute (JNCI).

Dr. Gokul Das, associate professor of oncology in the department of pharmacology and therapeutics and co-director of the breast disease site research group at Roswell Park, is excited at the possibility that tamoxifen could possibly be repurposed and on the market to treat triple-negative breast cancer (TNBC) in a few years. As he said, “We are particularly pleased to see that a readily available drug that has safely been given to hundreds of thousands of patients with or at risk for other types of breast cancer may be used to treat a disease subtype for which there are no effective therapies at present. None of the existing drug therapies have worked. Chemotherapy is usually used, but eventually the tumors metastasize.”

One reason TNBC is so aggressive and difficult to treat is “its ability to disarm proteins that suppress tumors and mutate them into tumor drivers,” Das explained. To understand this process, Das and his colleagues decided not to focus on the fact that these TNBC tumors lacked the estrogen receptor (ER-alpha), progesterone receptor (PR) and HER2 proteins, but rather on what they do have: an alternate estrogen receptor, ER-beta. In collaboration with an international team of researchers, they discovered that a widely used breast cancer drug, tamoxifen, can turn the ER-beta protein into a double agent capable of disrupting the processes that typically make TNBC tumors so devastating.

FDA-approved for the treatment and prevention of ER-alpha-positive breast cancers, tamoxifen is the oldest and most-prescribed selective estrogen receptor modulator. However, it was not thought to be effective against TNBC tumors because it targets ER-alpha, one of the proteins they lack. Das and his colleagues believe that tamoxifen, which has been broadly studied and well tolerated, can be used to target ER-beta.

The major mechanism behind most TNBC tumors is the mutation of an important tumor suppressor, the TP53 protein (also known as p53). When there is TNBC with normal TP53, ER-beta binds to the protein, disabling its tumor-suppressing capabilities and causing aggressive tumor behavior. According to Das, in TNBC with mutated TP53, ER-beta functions as a tumor suppressor by binding to mutated TP53, keeping it from functioning as a tumor driver.

Researchers in Das’ lab showed that ER-beta directly binds to TP53 and influences its function. Subsequent actions depend on the kind of TP53 the tumor cells have. ER-beta can have completely opposite functional capabilities, depending on whether the TP53 present in the tumors is normal or mutated.

Initial preclinical studies done on mice showed that tamoxifen increases binding of ER-beta to mutated TP53 in TNBC, leading to death of cancer cells. By analyzing a large breast cancer patient database, the researchers found that high levels of ER-beta in TNBC with mutated TP53 are associated with a more favorable prognosis. Now they are planning to use different dosages of tamoxifen and implanting patient-derived tumors in the mice, Das said.

“We have uncovered what we believe is the first known prognostic marker for triple-negative breast cancer, opening up an important opportunity to repurpose tamoxifen to treat TNBC,” he remarked. “This form of cancer represents 15 to 20 percent of all breast cancer cases.”

The researchers anticipate moving this work forward with a clinical trial to validate and further assess the laboratory findings. They want to determine whether tamoxifen might be used in combination with other therapy.

Das hopes to proceed quickly with Phase 1 and 2 clinical trials. Toxicology studies will not be needed, given that tamoxifen is already on the market.

He concluded, “We’re hoping that getting FDA approval will be easy and fast, because we’re repurposing an existing drug for a new mechanism. It’s a precision medicine application for a targeted group with a great need.”