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Under the Microscope: A new direction to stop breast cancer from coming back

About a third of all cancers diagnosed in women each year are breast cancers. The vast majority — 70% to 80% — of these tumors are estrogen receptor positive (ER+), which means they use the hormone estrogen to grow. Although ER+ breast cancer is often treatable with estrogen-blocking tamoxifen or other endocrine therapies, many patients eventually develop endocrine resistance that can lead to recurrence.

With funding from the V Foundation, Kexin Xu, PhD, from Mays Cancer Center at the University of Texas Health in San Antonio, is working to find new therapies that could circumvent this common form of treatment resistance and stop breast cancer from coming back. Her work may even uncover ways to make ER+ tumors more responsive to existing cancer treatments.

“About 30% to 40% of patients with localized ER+ tumors, and nearly all patients with ER+ metastatic breast cancer, will develop resistance to hormone therapies like tamoxifen,” said Xu. “This is why we’re very interested in finding new therapeutic options for patients with therapeutic-resistant breast cancer.”

Epigenetics could be key

At the heart of Xu’s strategy is an area of science called epigenetics that has gained substantial attention in cancer research. Epigenetic changes are chemical modifications that alter how genes are expressed without changing the genetic code. Because these changes are reversible, it is possible to use drugs to change cancer-linked epigenetic patterns back into normal patterns. In fact, drugs that work this way are already being used to treat other types of cancers.

“A lot of studies have suggested that epigenetic abnormalities play a very important role in the development of endocrine resistance,” said Xu. “Thus, we think epigenetics may represent a new direction for developing drugs for endocrine resistant ER+ breast cancer.”

In earlier work, Xu’s team identified an epigenetic enzyme called EZH2 as a very promising therapeutic target for treatment-resistant metastatic breast cancer. Experiments using an FDA-approved drug that inhibits EZH2-mediated epigenetic abberations also showed encouraging initial results.

For their V Foundation project, the researchers are digging deeper into how this drug works to put the brakes on breast cancer. They also developed a new breast cancer mouse model in which tissue from a patient with ER+ breast cancer is implanted into the mouse and moved from an endocrine sensitive to resistant status. Although they can be difficult to establish, this type of mouse model can be very useful for discovering and testing new therapies because the tumors are so similar to those found in patients.

Reversing treatment resistance

Using their new mouse model, Xu and colleagues found that the FDA-approved EZH2 inhibitor slowed the growth of ER+ breast tumors, especially tumors with endocrine resistance. They also observed that an EZH2-targeting drug can change the tumor microenvironment in a way that may make ER+ breast cancer more responsive to immunotherapy, a type of treatment that stimulates the body’s own immune system to attack cancer.

“This is an exciting finding because ER+ cancers usually don’t respond to immunotherapy,” said Xu. “We are now studying how these EZH2 inhibitors might synergize with immune checkpoint inhibitors to block the endocrine resistant breast cancer. Since both therapies are already FDA-approved, this combination therapy could move quickly into clinical testing.”

The researchers also developed new EZH2 inhibitors that show stronger effects against endocrine resistant breast cancer than the currently approved ones. They plan to use their new mouse models to test these promising drugs further.

“The support from V Foundation was key for developing the new models, which are an invaluable system for not only testing EZH2 inhibitors but also some other promising treatments,” said Xu. “This gives our lab a very unique tool that puts us in a priority position to carry out certain types of research.”

Xu says that the V Foundation support also allowed her team to collect the preliminary data necessary to expand into new research areas and gain new funding resources. This data has already helped them secure funding from the NIH, the Susan G. Komen Breast Cancer Foundation and the Mays Cancer Center.

To help fund important breast cancer research through the V Foundation, give through our Clea Shearer Breast Cancer Research Fund.