Powerful Drug Combo Gangs Up to Tackle Triple-Negative Breast Cancer

In the hunt for novel treatments against an aggressive form of breast cancer, University of Michigan researchers recently combined a new protein inhibitor with a chemotherapy drug.

The result: a powerful combination that led to cancer cell death.

Triple-negative breast cancer is a subtype that does not express hormone receptor, or HER2. It occurs in about 15 percent of patients with breast cancer. This subtype tends to be more aggressive, and targeted therapeutic treatment options are lacking.

In this work, the drugs were tested separately in triple-negative breast cancer cell lines and in mice with the disease. Researchers then implemented the treatments together.

That combination, they found, produced a synergistic effect that was more effective than either drug alone: Cancer cells treated with the drug combination were less likely to multiply or spread in cell culture and were less viable in an animal model.

Past discoveries drove the pairing.

Preliminary data had shown that inhibiting proteins called cyclin-dependent kinases, or CDKs, might be effective against triple-negative breast cancer. In this study, published in Oncotarget, researchers tested a pharmaceutical-grade CDK inhibitor called CYC065.

Additionally, they used the chemotherapy drug eribulin, which had shown promise in prior clinical trials for the treatment of triple-negative breast cancer.

"In this pre-clinical study, we showed that the combination of CYC065 and eribulin had a synergistic effect against the growth and progression of triple-negative breast cancer," says study author Jacqueline S. Jeruss, M.D., Ph.D., director of the Breast Care Center at the University of Michigan Rogel Cancer Center. "New therapeutic targets and treatment strategies are crucial to improve outcomes for women with this aggressive breast cancer subtype."

A longtime endeavor

From the early days of her career, Jeruss was interested in how signaling pathway alterations could affect the development of breast cancer.

What makes a mammary cell change to allow for lactation but then regress when that function is no longer needed? What orchestrates cell regulation to allow for such carefully mediated physiologic changes?

And, perhaps most crucial, what processes occur over time that cause the cellular deregulation leading to cancer development in certain patients but not in others?

Her work led her to the implementation of CDK inhibitors for the treatment of triple-negative breast cancer. Jeruss found that these drugs could help block the harmful impact of overexpression of cyclin E/CDKs — cancer-promoting proteins that were inhibiting the tumor-suppressant action of the TGF-beta/SMAD3 pathway. CDK inhibitors, then, can facilitate cancer cell death.

The current study affirms this. The combination of CYC065 with eribulin resulted in less-viable triple-negative breast cancer cells, smaller tumor colonies, decreased cell migration and small tumor size in an animal model.

U-M researchers also identified transcription factors that were affected by CYC065. These processes probably work together to promote cancer cell death.

"We have begun to identify a network of vulnerable and targetable signaling components within the triple-negative cancer cells that can be exploited with CDK inhibitor and chemotherapy treatment to promote triple-negative breast cancer cell death," Jeruss says.

The next step, she adds, is for researchers to develop a clinical trial to test the drug combination in patients with triple-negative breast cancer.