Researchers unveil experimental compound to block therapeutic target in blood cancer

Researchers at the UNC Lineberger Cancer Center have discovered an overactive cell signal that contributes to tumor growth in aggressive blood cancer. They have also developed an experimental treatment to block the signal and slow tumor growth.

The researchers reported in the newspaper Proceedings of the National Academy of Sciences they identified a new therapeutic target for primary effusion lymphoma, a type of non-Hodgkin lymphoma caused by Kaposi's sarcoma-badociated herpesvirus infection, also known as human herpesvirus.

"We found a protein called Tyro3 that was highly upregulated and expressed in a non-Hodgkin's lymphoma subtype, called primary effusion lymphoma," said Blossom Damania, Ph.D., vice-dean of research at the University of Toronto. UNC School of Medicine, Cary C. Boshamer Distinguished Professor of Microbiology and Immunology and co-director of UNC Lineberger programs in Virology and Global Oncology. "We also developed a compound that targeted Tyro3 and found that it had killed primary effusion lymphoma cells and tumors."

Primary effusion lymphoma is a very aggressive subtype of non-Hodgkin's lymphoma, a type of blood cancer involving abnormally growing white blood cells.

"Patients with primary effusion lymphoma have a poor prognosis with a median survival of about six months after diagnosis," said Jason Wong, the newspaper's first author and graduate student of the Department of Microbiology and the Department of Microbiology. immunology of the UNC School of Medicine. "Given that current treatment options may be ineffective, the priority is to find new therapeutic targets.

In their recent study, Damania and colleagues searched for cellular signals called hyperactive kinases in primary effusion lymphomas as well as other types of non-Hodgkin's lymphoma. They collaborated with Gary Johnson, Ph.D. of UNC Lineberger, Distinguished Professor at the Faculty of Medicine at the University of British Columbia, to characterize the activity of kinase signals in cancer cells. Kinases help control cell signaling, inviting cells to grow and divide. Their studies showed that Tyro3 kinase was particularly overactive in primary effusion lymphoma cells compared to normal cells, and they found that it could activate a pathway promoting cancer survival.

When they treated the cells with a compound that they developed, UNC3810A, they found an activation of dose-dependent cell death and a significant suppression of tumor growth. The compound was developed in the laboratory of Xiaodong Wang, Ph.D., Associate Professor at UNC Lineberger, Associate Professor of Research at the UNC Eshelman School of Pharmacy and Director of Medicinal Chemistry Center of the United States. UNC for Integrative Chemical Biology and Drug Discovery.

"In this study, UNC3810A was used as an in vivo tool compound to understand the biological roles of Tyro3 in primary effusion lymphoma," Wang said. "The work of optimizing the UNC3810A preclinical candidate will continue in my laboratory."

"We have identified a new target in a subtype of non-Hodgkin's lymphoma, which is also positively regulated in other types of cancer besides lymphoma, so the drug we developed can potentially be used to several cancers, "said Damania.