Double-duty drug discovery

JIB-04 suppresses adverse cardiac remodeling

What if the same class of drugs could improve the outlook for lung cancer and heart disease patients? UT Southwestern researchers recently published two papers suggesting just that.

“Targeting members of the Jumonji KDM enzyme family with an inhibitor can make radiation-resistant tumors more susceptible to treatment. The same agent can also prevent or overcome heart enlargement and fibrosis (tissue stiffening) in heart disease,” says Dr. Elisabeth Martinez, Assistant Professor of Pharmacology, an Investigator in the Hamon Center for Therapeutic Oncology Research, and a corresponding author on both studies, which were done in mice.

KDM is the acronym for histone lysine demethylase. The Jumonji KDM family gets its name from a Japanese word for “cruciform” because Japanese researchers noticed that developing Jumonji mutant mice had a crosslike pattern of grooves in the tissue plates destined to become neural tubes.

Changing DNA packaging

Drs. Elisabeth Martinez, Zhi-Ping Liu, Qing-Jun Zhang, and Tram Anh Tran
(l-r) Drs. Elisabeth Martinez, Zhi-Ping Liu, Qing-Jun Zhang, and Tram Anh Tran

Since both cancer and heart hypertrophy (wall thickening) reprogram the expression of genes, the UT Southwestern researchers used multiple approaches to inhibit Jumonji enzymes. These enzymes change gene expression by affecting how DNA is packaged. The approaches included the pharmacological inhibitor JIB-04, which the Martinez lab identified in 2013 through a small-molecule screen conducted at the National Center for Advancing Translational Sciences’ Chemical Genomics Center in Bethesda, Maryland.

The first of the two new studies, published Oct. 23 in Cell Reports, found that inhibitors affecting one subfamily of Jumonji enzymes could markedly increase the response to radiation therapy in tumors that were otherwise radiation-resistant. The study also found that human tumors expressing high levels of Jumonji enzymes are more resistant to radiation treatment.

“We were measuring levels of Jumonji enzymes in human tumors that had been biopsied or surgically removed. In patients who had responded well to radiation, there were low levels of the enzyme in their tumors. In patients who had a poor response to radiation treatment, there were high levels of the enzyme,” Dr. Martinez says.

“More than half of all tumors are typically treated with radiation. Since many tumors are already resistant to radiation or become so, this finding could eventually translate into more effective responses, with fewer side effects,” she adds. “JIB-04 significantly prolonged survival of mice with tumors treated with the inhibitor plus radiation, extending the life span for many weeks compared with the individual treatments alone.”

Beating heart disease

Dr. Zhi-Ping Liu, Associate Professor of Internal Medicine and Molecular Biology, led the second new study – published in Nature Communications in December – in collaboration with Dr. Martinez. Using a mouse model that mimics human heart disease caused by high blood pressure, that study found that JIB-04 suppressed changes to the heart typically seen in disease, including the thickening of the walls of the left ventricle and the scarring of heart muscle, known as fibrosis. Left ventricular hypertrophy and fibrosis are major risk factors for heart failure, she explains.

The double story is that, surprisingly, targeting members of the Jumonji KDM family with the same potential drugs can block DNA repair in cancer so that radiation works much better, and can also prevent or overcome heart hypertrophy.
Dr. Elisabeth Martinez

“Our study provides a proof-of-principle for pharmacological targeting of the Jumonji enzymes as an effective strategy to counter left ventricular hypertrophy and myocardial fibrosis,” Dr. Liu says, adding that their finding also describes a pathway driven by Jumonji enzymes associated with pathological cardiac remodeling upon heart injury.

The Jumonji inhibitors prevent the removal of methyl groups (demethylation) from histones, the proteins that package DNA, although the inhibitors probably work through different target pathways in cancer and heart disease, the researchers say.

“In both studies, the agent we identified exerted its effects by blocking the action of the Jumonji KDM enzymes responsible for erasing methylation marks on the histones that package DNA. So, inhibition of the enzymes causes accumulation of histone methylation in both cases,” Dr. Liu says.

Surprising double story

In cancer, radiation usually causes double-strand breaks in tumor cells’ DNA and changes the methylation of certain histones, triggering repairs that allow the cancer cells to survive, explains Dr. Martinez. “The Jumonji inhibitors block this repair process, causing methylation at defined histone loci. Unable to repair the DNA breaks, the cancer cells die.”

Normal heart vs enlarged heart
JIB-04 suppresses adverse cardiac remodeling

In heart disease, pathological organ remodeling upon cardiac injury leads to certain genes being turned on or off incorrectly, partly through the action of Jumonji KDMs, resulting in reduced methylation of a specific histone (H3K9), and upregulation of growth-promoting and fibrotic genes. JIB-04 inhibits these Jumonji KDMs, thus suppressing adverse heart remodeling, she adds.

“The double story is that, surprisingly, targeting members of the Jumonji KDM family with the same potential drugs can block DNA repair in cancer so that radiation works much better, and can also prevent or overcome heart hypertrophy,” Dr. Martinez says.

The Cell Reports study received support from the National Institutes of Health (NIH), the Department of Defense (DOD), the Cancer Prevention and Research Institute of Texas (CPRIT), The UT Southwestern Circle of Friends, and The Welch Foundation. That study’s first author is Dr. Juan Bayo, a postdoctoral fellow in the Martinez lab.

The Nature Communications study received support from NIH, DOD, CPRIT, The Welch Foundation, and the American Heart Association. Its three co-first authors are Dr. Qing-Jun Zhang, a Research Scientist in the Liu laboratory, Dr. Tram Anh Tran of the Martinez laboratory, and Dr. Ming Wang, a visiting senior research fellow in the Liu laboratory from the Zhujiang Hospital, Southern Medical University, China. Multiple other scientists contributed to both studies.