Enzyme-Inhibitor May be Shutting Off Brain Cancer Fighting Proteins

Researchers evaluate why early trials of dasatinib did not give conclusive results.

Mayo Clinic researchers have found that using dasatinib to slow down glioblastoma tumors inhibits both harmful and helpful proteins.

Dasatinib, used to treat certain types of blood cancers, was tested to see if it could also slow the growth of glioblastoma, a deadly form of brain cancer. No beneficial results were seen in the early clinical trials, and Mayo Clinic researchers sought to figure out why.

Dasatinib is an Src-family kinase (SFK) inhibitor, which shuts down the Src proteins - Src, Fyn, Yes, and Lyn - that are believed to be primarily responsible for the metastasis of tumors into the bloodstream.

In early trials, researchers used dasatinib to shut off all Src inhibitors. Further studies into these Src family members show that not all of them function the same way.

Researchers conducted trials on mice with glioblastoma, using dasatinib to shut off specific Src family members. When dasatinib shut down Src or Fyn, there was no change in survival. When Yes was shut down, survival increased; when Lyn was shut down, survival decreased.

These results show that while Yes promotes tumor growth, Lyn actually inhibits it. Those patients with higher expressions of Yes would benefit more from dasatinib, while those expressing more Lyn would be harmed by it. Testing dasatinib on tumor samples of individual patients may show that some are more eligible for dasatinib than others.

"The last thing we want to do is target both the good and the bad with dasatinib," said Panos Anastasiadis, PhD, the study's senior author. "In the long run, developing a drug that targets Yes, but has no effect on Lyn, could prove a much more effective therapy for gliomas."

These results explain why early dasatinib trials gave no conclusive results. Turning off all Src inhibitors may not do as much good as originally thought, since it seems that targeting all Src inhibitors not only turns off the bad ones, but also the good ones.

The research team is now examining results from a Mayo Clinic study that combined dasatinib with bevacizumab (Avastin), which restricts blood flow to tumors.

These findings were originally published in Molecular Oncology, 2015.