JAPANESE

Next Generation Research Incubator

Cancer Epigenome Center for Elucidation of Cancer and Development of Small Molecules for Clinical Application

A new center aims to combat cancer by rewriting the epigenetic modifications harbored by tumor cells

Cancer is thought of as a genetic disease, with mutations to a cell’s DNA causing a normal cell to give birth to a malignant tumor. Yet epigenetic alterations, which leave the DNA sequence intact, can be just as important in a cell’s transformation to cancer. Even though epigenetic regulation through mechanisms such as methyl tags and histone modifications does not alter the DNA sequence, it can chemically modify the genome to signal which genes should be turned on and off. When tumor-suppressor genes are silenced or oncogenes are activated in this way, many different forms of cancer can result.

Fortunately for medicine, epigenetic alterations are not permanent. They can be undone to prevent or reverse cancer, leaving a cell with its entire complement of normal DNA intact.

This is exactly what researchers at the Cancer Epigenome Center are striving to do. Led by Atsushi Kaneda, the center is seeking to understand the various epigenetic drivers that contribute to different types of cancer and then develop new drugs that overturn these effects.

“We will explain key epigenomic aberrations and their molecular causes,” says Kaneda. “And then, taking advantage of small molecules that bind to DNA in a sequence-specific manner, we will develop drugs that can rewrite the accumulated epigenomic aberrations or prevent them accumulating in targeted genomic regions.”

Unraveling molecular mechanisms

Kaneda points to ongoing investigations of gastric cancer as an example of this strategy in action. Patients with this cancer exhibit different levels of DNA methylation in their tumor cells, depending on the pathogen responsible for the disease. The cancer-causing bacterium Helicobacter pylori is one source of irregular methylation, infection with Epstein Barr virus is another. Both seem to have profound epigenetic impacts on stomach cells, leading to the silencing of many tumor suppressors.

Kaneda and his colleagues are using clinical samples and cell experiments to unravel the molecular mechanisms that induce hyperactive methylation patterns following infection with these pathogenic agents. They ultimately hope to stop the process in its tracks.

Similar projects are ongoing to combat colorectal cancers — which Chiba researchers have shown can be categorized into three types, depending on methylation levels — as well as blood cancers and other types of tumor.

With an eye to developing novel therapeutics, chemists at the Cancer Epigenome Center are working on new methods to efficiently synthesize molecules that can act on epigenetic aberrations. One such group of molecules is the pyrrole-imidazole polyamides. These molecules can bind to DNA at specific sites in the genome, and when coupled to an epigenetic inhibitor they can prevent methylation-based gene silencing. Kaneda hopes to deploy the molecules to edit the epigenome at targeted regions to regulate tumor formation.

The Cancer Epigenome Center includes researchers from a wide range of backgrounds and specialties. This multidisciplinary team approach, says Kaneda, is essential for turning the center’s discoveries into clinically meaningful treatments and diagnostic tools. “We will help determine the mechanisms of cancers and develop new cancer drugs through collaborating with experts in medicine, physics and pharmacy,” he says.