A new target for triple-negative breast cancer?
Chen Lab tackles hard-to-treat disease

Early-stage breast cancer can be curable, but one type presents major treatment challenges: triple-negative breast cancer (TNBC). “Triple negative” means these tumors lack the receptors for estrogen, progesterone and HER2, so TNBC patients don’t have access to important targeted therapies, such as Herceptin or Tamoxifen.

As a result, treating TNBC is like climbing a mountain without hand or footholds. There’s nothing to latch onto, keeping TNBC survival rates well below those of other types of breast cancer. To complicate matters, TNBC often learns to resist existing treatments. And though TNBC may sound like a single cancer, it’s really many.

“TNBC is actually many different kinds of cancer,” says Hongwu Chen, professor in the Department of Biochemistry and Molecular Medicine and a Cancer Center researcher. “Some of them are very aggressive and are more likely to relapse after treatment.”

But Chen may have a lead on a potential new target against TNBC: ROR-γ (ROR-gamma). This molecule, a member of the same protein family that includes estrogen and progesterone receptors, may play a significant role in TNBC growth.

“Our study in 2016 established ROR-γ as an important player in prostate cancer,” says Chen. “Continued study showed it plays a role in other cancers, including breast cancer and particularly triple-negative breast cancer.”

Chen’s early research has been promising, and was recently recognized by the National Cancer Institute (NCI) with a five-year, $2.16 million grant. The NCI wants to close the survival gap between TNBC and other breast cancers, and hitting ROR-γ may be a path forward.

The ROR-γ story

Chen’s lab has been following a number of clues that ROR-γ could be a good therapeutic target. Previous studies have shown the protein is overexpressed in some cancers, including prostate and TNBC. This added activity could be enabling rampant tumor growth.

ROR-γ is a nuclear hormone receptor protein. In other words, it’s activated by the human body’s hormonal signals and turns on specific genes.

“Cancers such as TNBC have hyper-activated cholesterol biosynthesis that allows tumor cells to make a lot of it, which is in turn used as a component in their cell membranes to allow rapid tumor growth,” says Chen. The NCI grant will allow Chen’s lab to firmly connect the nuclear hormone receptor to the abnormal cholesterol synthesis in TNBC.

The receptor protein also has a unique shape that makes it an attractive target. For these and other reasons, ROR-γ has been targeted by pharma-ceutical companies, mostly for its role inside a group of immune T cells, to treat autoimmune conditions, like psoriasis. There have been a number of clinical trials but no FDA approvals yet. Still, research by the Chen lab has shown ROR-γ could be a good protein to target for other conditions, including TNBC.

Developing an inhibitor

While much is known about ROR-γ, there’s still work to do. The Chen lab hopes to leverage the NCI grant to learn more about ROR-γ and how it contributes to TNBC. That means dissecting the protein’s biology to better understand which genes get turned on and how that might drive tumor growth, metastasis and treatment resistance.

Ultimately, they want to test molecules that shut down ROR-γ in the same way Herceptin turns off HER2 and Tamoxifen controls estrogen receptors.

“The grant will allow us to more deeply study the protein function and how it controls essential pathways in TNBC,” says Chen. “Beyond that, we want to test small molecule inhibitors in different models, including patient-derived xenografts, and see whether they can have a strong anti-tumor effect.”