In a new report of research, scientists at Johns Hopkins University School of Medicine and Johns Hopkins Kimmel Cancer Center say they have found a potential therapeutic target that can boost the potency of a chemotherapy used to treat certain cancers.

The researchers say the target, a protein called DCTPP1 that breaks down modified pieces of DNA and stabilizes the genome, degrades the quality of decitabine, a chemotherapy commonly used to treat bone marrow disorders and acute myeloid leukemia. In a study of prostate cancer cells, the scientists say that blocking DCTPP1’s function with newly identified inhibitors helped improve decitabine’s ability to kill off cancer cells.  

A report of the National Institutes of Health-funded research was published June 15 in Proceedings of the National Academy of Sciences.

“By taking a close look at the atomic structures of DCTPP1, we were able to find a class of inhibitors that can stop this protein in its tracks and improves the activity of an existing type of anti-cancer drug in prostate cancer cells,” says co-corresponding author James Berger, Ph.D., director of the Johns Hopkins Medicine Institute for Basic Biomedical Sciences and the Michael and Ann Hankin and Partners of Brown Advisory Professor in Scientific Innovation.

Decitabine works by incorporating itself into the genome and killing cancer cells. DCTPP1, meanwhile, finds these chemically modified pieces of DNA and degrades them, limiting decitabine’s abilities to find and target cancer cells, the scientists say.

Johns Hopkins Medicine scientists are investigating ways to improve decitabine’s potency and use it to treat more cancers, including prostate cancer, which can develop into a more aggressive, castration-resistant form. Castration-resistant prostate cancer affects 10% to 20% of patients with prostate cancer, the researchers say. In many cases, this form of cancer may spread to the bones, lymph nodes, liver and other organs, and has an average five-year survival rate of 28%, according to Johns Hopkins Medicine.

“Our research can lead to better, more effective treatments for more patients with prostate cancer,” says co-corresponding author Vasan Yegnasubramanian, M.D., Ph.D., professor of oncology, pathology, and radiation oncology and molecular radiation sciences at the Johns Hopkins Kimmel Cancer Center, and director of inHealth Precision Medicine at Johns Hopkins Medicine. “Prior studies have shown that prostate cancer cells showed resistance to low doses of decitabine exposure, and so we sought out whether we could improve how cells respond to this drug by finding new ways to block DCTPP1.”

To begin the research, Yegnasubramanian, who had been looking to DCTPP1 as a potential target that may improve decitabine, approached Berger, a biophysicist, to visualize how this protein interacts with chemical ligands. The scientists started off by screening 10,000 chemical compounds, and identified three classes of compounds that could inhibit the activity of the DCTPP1 protein.

The investigators then used X-ray crystallography to determine the atomic crystal structures of these small molecules and visualize how they block enzyme activity, revealing that each class of inhibitor associates with DCTPP1 in a specific nucleotide-binding pocket. From there, they combined these inhibitors with the chemotherapeutic decitabine, adding them to cultures of living prostate cancer cells from a publicly available cell line. Their experiments indicated that when combined with these new inhibitors, decitabine was more successful at killing off the prostate cancer cells.

The scientists say further studies may determine whether these inhibitors can be made more potent to further improve decitabine’s ability to stop the spread of other forms of cancer cells.

“We can help patients with cancer live longer, healthier lives by finding new ways to improve already existing cancer drugs, including decitabine,” says William Nelson, M.D., Ph.D., director of the Johns Hopkins Kimmel Cancer Center and a co-author of the paper. 

In addition to Berger, Yegnasubramanian and Nelson, other Johns Hopkins scientists who contributed to this paper include Glenn Hauk and Jianyong Liu.

Funding for this research was provided by the National Cancer Institute, part of the National Institutes of Health (R35-CA263778, P50CA272391 and P30CA006973). Additional support was provided by the Commonwealth Foundation, the Irving Hansen Foundation and the Prostate Cancer Foundation.