Dacogen Shows Promise in Triple-negative Breast Cancer Animal Models, Study Shows

Dacogen Shows Promise in Triple-negative Breast Cancer Animal Models, Study Shows
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Dacogen (decitabine), a medicine used for treating a group of blood cell disorders, may be a potential new treatment for women with triple-negative breast cancer, including those who failed chemotherapy, a study suggests.

The study, “DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine,” was published in The Journal of Clinical Investigation.

“There is a great need to identify additional treatment options for triple-negative breast cancer, which is one of the most difficult to treat subtypes of breast cancer,” Liewei Wang, MD, PhD, and senior author of the study, said in a press release.

“The study is a demonstration that we can take advantage of many existing FDA approved drugs to expand their usage by better understanding the mechanisms of how they work and applying them to other cancers,” she added.

Dacogen is an inhibitor of proteins called DNA methyltransferases, which are enzymes that add chemical groups to DNA. This is important for regulating cell replication and differentiation. The compound works by incorporating itself onto DNA during cell proliferation, trapping methyltransferases and reducing DNA methylation levels.

In cancer, this is thought to reactivate tumor-suppressor genes, which gives Dacogen it’s anti-tumor effects. 

Importantly, the medicine is highly toxic for rapidly dividing cells such as tumor cells, while non-proliferating cells are relatively insensitive to the drug.

The present study was part of the ongoing work in a clinical trial called BEAUTY (NCT02022202), whose goal is to better understand the reasons why some breast cancers do not respond to standard chemotherapy.

Researchers from BEAUTY generated cancer models called xenografts — in which cells from a patient’s tumor are implanted into a mouse model — from patients with triple-negative breast cancer treated with chemotherapy.

They found that Dacogen’s ability to kill triple-negative breast cancer cells increased depending on the amount of DNA methyltransferases present in the cancer. This made methyltransferase levels good predictors of whether a cancer was likely or not to respond to Dacogen treatment.

Researchers determined that DNA methyltransferase levels could potentially serve as biomarkers to guide treatment selection in the clinic and to identify which patients would benefit from the therapy.

Knowing beforehand who is more likely to respond to treatment is particularly critical for patients with triple-negative breast cancer, who fail to respond to several therapies including hormone and targeted therapy.

Researchers also observed that Dacogen effectively targeted cancer cells even at a low therapeutic dose, meaning that treatment with Dacogen could potentially lead to fewer adverse events. This would allow for longer treatments, which could lead to better therapeutic effectiveness.

An important observation was that Dacogen treatment was able to kill patient-derived tumors even if those tumors were resistant to chemotherapy.

“Patients whose tumor does not respond well to chemotherapy are known to be at significantly increased risk of recurrent breast cancer and death,” said Judy Boughey, MD, a Mayo Clinic breast surgeon and one of the study’s authors.

Triple-negative breast cancer patients with high DNA methyltransferase levels and resistance to standard chemotherapy “may still benefit from decitabine,” researchers wrote. “Future clinical studies are required to test decitabine or decitabine-like drugs in high-risk [triple negative breast cancer] patients.”

Meanwhile, the team plans to study the impact of Dacogen treatment in a prospective clinical trial called BEAUTY2, which focuses on women with triple-negative breast cancer resistant to chemotherapy.

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