Its complex name is consistent with its challenging nature. Activated B-cell-like diffuse large B-cell lymphoma is among the toughest, most aggressive forms of lymphoma to treat.

Hua Yu is investigating a strategy against an aggressive form of lymphoma. (Photo by Walter Urie)

A cross-disciplinary team of City of Hope researchers may have found a new way to undercut the disease, however, through an innovative genetic therapy. With the support of a three-year, $600,000 grant from The V Foundation for Cancer Research, the scientists aim to develop the potential therapy and ready it for clinical studies.

The strategy centers around a protein known as signal transducer and activator of transcription 3, or STAT3, which promotes this form of lymphoma.

Lymphoma cells, like many other cancer cells, often overproduce STAT3 — which promotes cancer growth and suppresses the immune system’s ability to fight cancer, explained Hua Yu, Ph.D., Tim Nesvig Lymphoma Research Fellow and professor in the Department of Cancer Immunotherapeutics and Tumor Immunology.

The scientists developed a molecule called a short interfering RNA, or siRNA, that shuts down lymphoma cells’ ability to make STAT3. Then they linked the siRNA to a short piece of DNA that binds to and activates a protein called Toll-like receptor 9, also called TLR9, which stimulates the body’s immune defenses.

“We were looking for a way to improve siRNA delivery,” said Yu, who is principal investigator on the grant. “By using TLR9, we realized we could get the siRNA into lymphoma cells more efficiently and at the same time stimulate an immune response.”

The team will test the new approach in mice with the human form of this B-cell lymphoma, looking at its ability to fight disease as well as resulting side effects. They also will screen the activity of other genes in the mice’s immune cells to determine if any of those genes can predict the drug’s effectiveness.

“We want to know how the drug affects other genes in the body, and we want to see if we can predict the drug’s ability to kill cancer cells by testing the chemistry and expression of genes in circulating immune cells,” Yu said.

She noted that preliminary studies supported by the W.M. Keck Foundation grant led to the current project funded by The V Foundation.

“We’re very happy that The V Foundation saw the value in our study,” Yu said. “We’ve had good results up to this point, and the foundation’s support will help us determine how well this therapy might work in humans.”

The V Foundation was founded by former North Carolina State University basketball coach and award-winning sports broadcaster Jimmy Valvano, who died of bone cancer in 1993 at age 47. The V Foundation has raised more than $100 million and awarded cancer research grants in 38 states and the District of Columbia since its inception.

Stephen J. Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, and Marcin Kortylewski, Ph.D., assistant professor in the Department of Cancer Immunotherapeutics and Tumor Immunology, are co-investigators on the grant. John J. Rossi, Ph.D., Lidow Family Research Chair in the Department of Molecular and Cellular Biology, serves as a project consultant.