31 July 2019

A new specific drug target for primary effusion lymphoma (PEL) – an aggressive type of non-Hodgkin’s lymphoma – has been discovered by a team from the University of North Carolina, USA.

First author Jason Wong explains: “Patients with primary effusion lymphoma have a poor prognosis with a median survival time of approximately six months post-diagnosis. Since current treatment options can be ineffective, finding new therapeutic targets is a high priority.”

The researchers looked for signalling proteins called kinases which were over-expressed in different forms of non-Hodgkin’s lymphoma. They found that a molecule called Tyro3 is “uniquely hyperactive” in patients with PEL, and appears to activate a pathway that promotes the cancer’s survival.

The researchers went on to test a selective Tyro3 inhibitor they had developed called UNC3810A. Experiments in cell lines demonstrated a dose-dependent activation of cell death. The use of the compound in mice carrying a PEL cell line resulted in significant suppression of tumour growth.

The study published in the Proceedings of the National Academy of Sciences.

Team leader Dr Blossom Damania says: “We found a protein called Tyro3 that's highly upregulated and expressed in a subtype of non-Hodgkin lymphoma, called primary effusion lymphoma. We also developed a compound that targeted Tyro3, and we found that it killed primary effusion lymphoma cells and tumors.”

The UNC3810A compound was developed by a team led by medicinal chemist Dr Xiaodong Wang. She explained: “UNC3810A was used as an in vivo tool compound to understand the biological roles of Tyro3 in primary effusion lymphoma in this study. The work towards optimising UNC3810A to preclinical candidate will be continued in my lab.”

Other tumour types also show increased production of Tyro3, so the researchers believe that the drug could potentially be used for multiple cancers in the future.

Source: Wong, J.P., Stuhlmiller, T.J., Giffin, L.C., Lin, C., Bigi, R., Zhao, J., Zhang, W., Bravo Cruz, A.G., Park, S.I., Earp, H.S., Dittmer, D.P., Frye, S.V., Wang, X., Johnson, G.L., Damania, B. (2019) “Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma”, PNAS, available from doi: 10.1073/pnas.1903991116


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